Heteroaryl Compounds For Kinase Inhibition

ABSTRACT

Compounds and pharmaceutical compositions that modulate kinase activity, including mutant EGFR and mutant HER2 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including mutant EGFR and mutant HER2 activity, are described herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 62/014,500, filed Jun. 19, 2014; which is incorporated hereinby reference in it entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on May 12, 2015, isnamed 477APCT_SL.txt and is 767 bytes in size.

BACKGROUND

Biological signal transduction refers to the transmission of stimulatoryor inhibitory signals into and within a cell leading, often via acascade of signal transmission events, to a biological response withinthe cell. Many signal transduction pathways and their biologicalresponses have been studied. Defects in various components of signaltransduction pathways have been found to account for a large number ofdiseases, including numerous forms of cancer, inflammatory disorders,metabolic disorders, vascular and neuronal diseases. These defects canoften occur at the gene level, where DNA insertions, deletions ortranslocations can, for example, cause cells to proliferateuncontrollably in the case of some cancers.

Signal transduction is often mediated by certain proteins calledkinases. Kinases can generally be classified into protein kinases andlipid kinases, and certain kinases exhibit dual specificities. Proteinkinases are enzymes that catalyze the phosphorylation of other proteinsand/or themselves (i.e., autophosphorylation) and can be generallyclassified based upon their substrate utilization, e.g.: tyrosinekinases which predominantly phosphorylate substrates on tyrosineresidues (e.g., KIT, erb2, PDGF receptor, EGF receptor, VEGF receptor,src, and abl), serine/threonine kinases which predominantlyphosphorylate substrates on serine and/or threonine residues (e.g.,mTorC1, mTorC2, ATM, ATR, DNA-PK, Akt), and dual-specificity kinaseswhich phosphorylate substrates on tyrosine, serine and/or threonineresidues.

Epidermal growth factor receptor (EGFR) belongs to a family of receptortyrosine kinases (RTKs) that include EGFR/ERBB1, HER2/ERBB2/NEU,HER3/ERBB3, and HER4/ERBB4. The binding of a ligand, such as epidermalgrowth factor (EGF), induces a conformational change in EGFR thatfacilitates receptor homo- or heterodimer formation, leading toactivation of EGFR tyrosine kinase activity. Activated EGFR thenphosphorylates its substrates, resulting in activation of multipledownstream pathways within the cell, including the PI3K-AKT-mTORpathway, which is involved in cell survival, and the RAS-RAF-MEK-ERKpathway, which is involved in cell proliferation. (Chong et al. NatureMed. 2013; 19(11):1389-1400).

Approximately 10% of patients with NSCLC in the US (10,000 cases/year)and 35% in East Asia are reported to have tumor-associated EGFRmutations. (Lynch et al. N Engl J Med. 2004; 350(21):2129-39). The vastmajority of NSCLC cases having an EGFR mutation do not also have amutation in another oncogene (e.g., KRAS mutations, ALK rearrangements,etc.). EGFR mutations mostly occur within EGFR exons 18-21, which encodea portion of the EGFR kinase domain. EGFR mutations are usuallyheterozygous, with amplification of mutant allele copy number.Approximately 90% of these mutations are exon 19 deletions or exon 21L858R point mutations. These mutations increase the kinase activity ofEGFR, leading to hyperactivation of downstream pro-survival signalingpathways. (Pao et. al. Nat Rev Cancer 2010; 10:760-774).

Small deletions, insertions or point mutations in the EGFR kinase domainhave been cataloged and described at length in the scientificliterature. See e.g., Sharma, Nat Re. Cancer 2007; 7:169 (exon 19mutations characterized by in-frame deletions of amino-acid 747 accountfor 45% of mutations, exon 21 mutations resulting in L858R substitutionsaccount for 40-45% of mutations, and the remaining 10% of mutationsinvolve exon 18 and 20); Sordella et al., Science 2004; 305:1163; andMulloy et al., Cancer Res 2007; 67:2325. EGFR mutants also include thosewith a combination of two or more mutations, such as those describedherein. For example, “DT” refers to a T790M gatekeeper point mutation inexon 20 and a five amino acid deletion in exon 19 (delE746_A750).Another common mutation combination is IT that includes the T790Mgatekeeper point mutation and the L858R point mutation in exon 21.

EGFR exon 20 insertions reportedly comprise approximately 4-9.2% of allEGFR mutant lung tumors (Arcila et al. 2013; 12(2):220-9; Mitsudormi andYatabe FEBS J. 2010; 277(2):301-8; Oxnard et al. J Thorac Oncol. 2013;8(2):179-84). Most EGFR exon 20 insertions occur in the region encodingamino acids 767 through 774 of exon 20, within the loop that follows theC-helix of the kinase domain of EGFR (Yasuda et al. Lancet Oncol. 2012;13(1):e23-31).

EGFR exon 20 insertion mutants, other than A763_Y764insFQEA, areassociated in preclinical models, for the most part, with lowersensitivity to clinically achievable doses of the reversible EGFR TKIs,erlotinib (Tarceva) and gefitinib (Iressa), and of the irreversible EGFRTKIs neratinib, afatinib (Gilotrif), and dacormitinib (Engelman et al.Cancer Res. 2007; 67(24):11924-32; Li et al. Oncogene2008:27(34):4702-11; Yasuda, et al. 2012; Yasuda et al. Sci Transl Med.2013; 5(216):216ra177; Yuza et al. Cancer Biol Ther. 2007; 6(5):661-7),and of the mutant-selective covalent EGFR TKIs WZ4002 (Zhou et al.Nature 2009; 462(7276):1070-4) and CO-1686 (Walter et al. Cancer Discov2013; 3(12):1404-15). The crystal structure of a representativeTKI-insensitive mutant (D770_N771insNPG) revealed that it has anunaltered ATP-binding pocket and that, unlike EGFR sensitizingmutations, it activates EGFR without increasing its affinity for ATP(Yasuda et al. 2013).

Patients with tumors harboring EGFR exon 20 insertion mutationsinvolving amino acids A767, S768, D770, P772 and H773 don't respond togefitinib or erotinib (Wu et al. Clin Cancer Res. 2008; 14(15):4877-82;Wu et al. Clin Cancer Res. 2011; 17(11):3812-21; Yasuda et al. 2012). Inretrospective and prospective analyses of patients with NSCLCs harboringtypical EGFR exon 20 insertions, most displayed progressive disease inthe course of treatment with gefitinib or erlotinib or afatinib (Yasudaet al. 2012; Yasuda et al. 2013).

HER2 mutations are reportedly present in ˜2-4% of NSCLC (Buttitta et al.Int J Cancer 2006; 119:2586-2591; Shigematsu et al. Cancer Res 2005;65:1642-6; Stephens et al. Nature 2004; 431:525-6). The most commonmutation is an in-frame insertion within exon 20. In 83% of patientshaving HER2 associated NSCLC, a four amino acid YVMA insertion mutationoccurs at codon 775 in exon 20 of HER2. (Arcila et al. Clin Cancer Res2012; 18:4910-4918). HER2 mutations appear more common in “neversmokers” (defined as less than 100 cigarettes in a patient's lifetime)with adenocarcinoma histology (Buttitta et al. 2006; Shigematsu et al.2005; Stephens et al. 2004). However, HER2 mutations can also be foundin other subsets of NSCLC, including in former and current smokers aswell as in other histologies (Buttitta et al. 2006; Shigematsu et al.2005; Stephens et al. 2004). The exon 20 insertion results in increasedHER2 kinase activity and enhanced signaling through downstream pathways,resulting in increased survival, invasiveness, and tumorigenicity (Wanget al. Cancer Cell 2006; 10:25-38). Tumors harboring the HER2 YVMAmutation are largely resistant to known EGFR inhibitors. (Arcila et al.2012).

Disclosed herein are compounds with inhibitory activity against a)mutant EGFR, such as EGFR having one or more exon 20 insertions, DT orLT, and b) mutant HER2 such as HER2 having a YVMA insertion mutation.Also disclosed are methods for preparing the compounds andpharmaceutical compositions containing them. In addition, methods aredisclosed for inhibiting mutant EGFR bearing an exon 20 insertionmutation or bearing a, DT or LT mutation, and for inhibiting mutantHER2, as well as methods of treatment of disease mediated by any ofthose mutant EGFR or HER2 proteins, including cases that are resistantto known treatments of care SUMMARY

Compounds are disclosed herein that are capable of inhibiting mutantEGFR proteins, e.g., EGFR having one or more mutations in the exon 20domain. In some embodiments, compounds disclosed herein selectivelyinhibit mutant EGFR, such as EGFR having one or more exon 20 mutations,over wild-type EGFR. In other embodiments, the compounds selectivelyinhibit mutant EGFR, such as EGFR having an exon 20 point mutationtogether with an exon 19 or exon 21 mutation. Such inhibitors can beeffective in ameliorating diseases and disorders associated with mutantEGFR activity.

Compounds disclosed herein are capable of inhibiting mutant HER2, e.g.,HER2 having one or more mutations in the exon 20 domain. In someembodiments, the disclosed compounds selectively inhibit mutant HER2,such as HER2 having one or more exon 20 mutations, over wild-type EGFR.Such inhibitors can be effective in ameliorating diseases and disordersassociated with mutant HER2 activity.

One aspect of the invention provides compounds of Formula I:

or a pharmaceutically acceptable form thereof, wherein:

A is selected from

-   -   X₁ is selected from N and CR₁;

X₂ is selected from N and CR₂;

X₃ is selected from N and CR₄;

each X₄ is independently selected from N and CR₇;

-   -   X₅ is selected from N and CR₈;

X₆ is selected from N and CR;

R₁ is selected from H, acyl, alkyl, alkenyl, alkynyl, alkoxy, aryloxy,alkoxycarbonyl, amido, amino, carbonate, carbamate, carbonyl, carboxyl,ester, halo, CN, NO₂, hydroxy, phosphate, phosphonate, phosphinate,phosphine oxide, mercapto, thio, alkylthio, arylthio, thiocarbonyl,sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, cycloalkyl,heterocyclyl, aryl, and heteroaryl, each of which is substituted with 0,1, 2, or 3 R₁₂;

R₂, R₃, and R₄ are each independently selected from H, alkyl, alkoxy,halo, CN, and NO₂, each of which is substituted with 0, 1, 2, or 3 R₁₂;

R₅ is selected from H, alkyl, alkenyl, alkynyl, —NR₁₀R₁₁, —OR₁₁, and—SR₁₁, each of which is independently substituted with 0, 1, 2, or 3R₁₂; or when R₅ is —NR₁₀R₁₁, then R₁₀ and R₁₁ can be taken together withthe nitrogen atom to which they are attached to form a heterocyclyl orheteroaryl group, each of which is substituted with 0, 1, 2, or 3 R₁₂;

R₄ and R₅ can be taken together with the carbon atoms to which they areattached to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl group,each of which is substituted with 0, 1, 2, or 3 R₁₂;

R₆ is selected from H, acyl, alkyl, amino, halo, CN, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl, each of which is substitutedwith 0, 1, 2, or 3 R₁₂;

each R₇ is independently selected from H, alkyl, alkenyl, alkynyl,alkoxy, amido, amino, carbonyl, ester, halo, CN, and NO₂, each of whichis substituted with 0, 1, 2, or 3 R₁₂; and wherein any two adjacent R₇groups can be taken together with the carbon atoms to which they areattached to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl ring,each of which is substituted with 0, 1, 2, or 3 R₁₂;

R₈ is selected from H, acyl, alkyl, amido, amino, carbamate, carbonyl,and urea, each of which is substituted with 0, 1, 2, or 3 R₁₂;

R₉ is selected from H, alkyl, alkenyl, alkynyl, alkoxy, amino, amido,ester, halo, CN, NO₂, cycloalkyl, heterocyclyl, aryl, and heteroaryl,each of which is substituted with 0, 1, 2, or 3 R₁₂;

each R₁₀ and R₁₁ are independently selected from H, acyl, alkyl,carbonyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, each ofwhich is independently substituted with 0, 1, 2, or 3 R₁₂; and

each R₁₂ is independently selected from acyl, alkyl, alkenyl, alkynyl,alkoxy, aryloxy, alkoxycarbonyl, amido, amino, carbonate, carbamate,carbonyl, ester, halo, CN, NO₂, hydroxyl, phosphate, phosphonate,phosphinate, phosphine oxide, thio, alkylthio, arylthio, thiocarbonyl,sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl.

In the following embodiments, all variables are as described for FormulaI and/or elsewhere below.

Formula I includes a compound of Formula Aa:

Formula I includes a compound of Formula Ab:

Formula I includes a compound of Formula Ac:

Formula I includes a compound of Formula Ad:

Formula I includes a compound of Formula Ae:

Formula I includes a compound of Formula Af:

Formula I includes a compound of Formula Ba:

Formula I includes a compound of Formula Bb:

Formula I includes a compound of Formula Bc:

Formula I includes a compound of Formula Bd:

Formula I includes a compound of Formula Be:

Formula I includes a compound of Formula Bf:

Formula I includes a compound of Formula Bg:

Formula I includes a compound of Formula Bh:

Formula I includes a compound of Formula Bi:

A method is also disclosed herein for treating cancer associated withone or more insertion or deletion mutations in the exon 20 domain ofEGFR or of HER2, comprising administering to a subject in need thereof,a therapeutically effective amount of a compound of Formula I.

A composition (e.g., a pharmaceutical composition) is also disclosedcomprising a compound as described herein and one or morepharmaceutically acceptable excipients. In some embodiments, providedherein is a method of inhibiting exon 20 mutant EGFR, comprisingcontacting the exon 20 mutant EGFR with an effective amount of acompound or pharmaceutical composition as described herein. In someembodiments, a method is provided for inhibiting exon 20 mutant EGFRwherein said exon 20 mutant EGFR is present in a cell. This inhibitioncan be selective for exon 20 mutant EGFR over wild type. In otheraspects, the inhibition can take place in a subject suffering from adisorder selected from various cancers, such as but not limited to,NSCLC, colorectal cancer, pancreatic cancer, and head and neck cancers.In some embodiments, a second therapeutic agent can be administered tothe subject.

In one aspect, provided herein are compounds of Formula I:

wherein:

A is selected from

-   -   X₁ is selected from

X₂ is selected from N and CR₂;

X₃ is selected from N and CR₄;

each X₄ is independently selected from N and CR₇;

-   -   X₅ is selected from N and CR₈;

X₆ is selected from N and CR₉;

-   -   each R₁ is independently selected from alkyl, alkenyl, alkynyl,        cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is        substituted with 0, 1, 2, or 3 R₁₂;    -   R₁′ is selected from H and alkyl, each of which is substituted        with 0, 1, 2, or 3 R₁₂;    -   R₂, R₃, and R₄ are each independently selected from H, alkyl,        alkoxy, halo, CN, and NO₂, each of which is substituted with 0,        1, 2, or 3 R₁₂;    -   R₅ is selected from H, alkyl, alkenyl, alkynyl, —NR₁₀R₁₁, —OR₁₁,        and —SR₁₁, each of which is independently substituted with 0, 1,        2, or 3 R₁₂; or when R₅ is —NR₁₀R₁₁, then R₁₀ and R₁₁ can be        taken together with the nitrogen atom to which they are attached        to form a heterocyclyl or heteroaryl group, each of which is        substituted with 0, 1, 2, or 3 R₁₂;    -   R₄ and R₅ can be taken together with the carbon atoms to which        they are attached to form a cycloalkyl, heterocyclyl, aryl, or        heteroaryl group, each of which is substituted with 0, 1, 2, or        3 R₁₂;    -   R₆ is selected from H, acyl, alkyl, amino, halo, CN, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl, each of which is        substituted with 0, 1, 2, or 3 R₁₂;    -   each R₇ is independently selected from H, alkyl, alkenyl,        alkynyl, alkoxy, amido, amino, carbonyl, ester, halo, CN, and        NO₂, each of which is substituted with 0, 1, 2, or 3 R₁₂; and        wherein any two adjacent R₇ groups can be taken together with        the carbon atoms to which they are attached to form a        cycloalkyl, heterocyclyl, aryl, or heteroaryl ring, each of        which is substituted with 0, 1, 2, or 3 R₁₂;    -   R₈ is selected from H, acyl, alkyl, amido, amino, carbamate,        carbonyl, and urea, each of which is substituted with 0, 1, 2,        or 3 R₁₂;    -   R₉ is selected from H, alkyl, alkenyl, alkynyl, alkoxy, amino,        amido, ester, halo, CN, NO₂, cycloalkyl, heterocyclyl, aryl, and        heteroaryl, each of which is substituted with 0, 1, 2, or 3 R₁₂;    -   each R₁₀ and R₁₁ are independently selected from H, acyl, alkyl,        carbonyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,        each of which is independently substituted with 0, 1, 2, or 3        R₁₂; and

each R₁₂ is independently selected from acyl, alkyl, alkenyl, alkynyl,alkoxy, aryloxy, alkoxycarbonyl, amido, amino, carbonate, carbamate,carbonyl, ester, halo, CN, NO₂, hydroxyl, phosphate, phosphonate,phosphinate, phosphine oxide, urea, cycloalkyl, heterocycloalkyl, aryl,and heteroaryl.

In the following embodiments, all variables are as described for FormulaI and/or in further aspects of the disclosure below.

A method is provided for treating cancer associated with mutant EGFR ormutant HER2, comprising administering to a subject in need thereof, atherapeutically effective amount of a compound of Formula I. In certainembodiments, compounds disclosed herein selectively modulate mutantEGFR, such as, but not limited to, EGFR having one or more insertion,point, or deletion mutations in the exon 19, 20, and/or 21 domain. Inother embodiments, compounds disclosed herein selectively modulatemutant HER2, such as, but not limited to, HER2 having one or moreinsertion, point, or deletion mutations in the exon 20 domain. In someembodiments, compounds disclosed herein selectively modulate mutant EGFRhaving one or more insertion mutations in the exon 20 domain. In otherembodiments, compounds disclosed herein selectively modulate mutant EGFRhaving one or more deletion mutations in the exon 20 domain. In otherembodiments, compounds disclosed herein selectively modulate mutant EGFRhaving one or more point mutations in the exon 20 domain. In otherembodiments, compounds disclosed herein selectively modulate mutant EGFRhaving one or more insertion or deletion mutations in the exon 19domain. In other embodiments, compounds disclosed herein selectivelymodulate mutant EGFR having one or more insertion, deletion or pointmutations in the exon 21 domain.

In some embodiments, disclosed compounds selectively inhibit mutantEGFR, having one or more insertion or deletion mutations, over wild-typeEGFR. In other embodiments, disclosed compounds selectively inhibitmutant EGFR having an exon 20 point mutation concomitantly with an exon19 deletion or an exon 21 point mutation. In a further embodiment,disclosed compounds selectively inhibit mutant EGFR having one or moreexon 19 deletion mutations. In other embodiments, compounds disclosedherein selectively inhibit mutant EGFR, having an exon 21 point mutation(e.g., L858R). By way of non-limiting example, the ratio of selectivitycan be greater than a factor of about 10, greater than a factor of about20, greater than a factor of about 30, greater than a factor of about40, greater than a factor of about 50, greater than a factor of about60, greater than a factor of about 70, greater than a factor of about80, greater than a factor of about 100, greater than a factor of about120, or greater than a factor of about 150, where selectivity can bemeasured by in vitro assays known in the art. Non-limiting examples ofassays to measure selectivity include enzymatic assays, cellularproliferation assays, and EGFR phosphorylation assays. In oneembodiment, selectivity can be determined by cellular proliferationassays. In another embodiment, selectivity can be determined by EGFRphosphorylation assays. In some embodiments, the mutant EGFR inhibitoryactivity of a compound as disclosed herein can be less than about 1000nM, less than about 100 nM, less than about 50 nM, less than about 30nM, or less than about 10 nM.

In some embodiments, a composition (e.g., a pharmaceutical composition)is provided comprising a compound as described herein and one or morepharmaceutically acceptable excipients. In some embodiments, providedherein is a method of inhibiting exon 20 mutant EGFR, comprisingcontacting the exon 20 mutant EGFR with an effective amount of acompound or pharmaceutical composition as described herein. In someembodiments, a method is provided for inhibiting exon 20 mutant EGFRwherein said exon 20 mutant EGFR is present in a cell. This inhibitioncan be selective for exon 20 mutant EGFR over wild type EGFR. In otheraspects, the inhibition can take place in a subject suffering from adisorder selected from various cancers, such as but not limited to,NSCLC, colorectal cancer, pancreatic cancer, and head and neck cancers.In some embodiments, a second therapeutic agent can be administered tothe subject.

Some embodiments provide a method of preparing a compound as describedherein.

Some embodiments provide a reaction mixture comprising a compound asdescribed herein.

Some embodiments provide a kit comprising a compound as describedherein.

Some embodiments provide a method for treating a disease or disorderdescribed herein, the method comprising administering a therapeuticallyeffective amount of a compound or pharmaceutical composition describedherein to a subject.

Some embodiments provide a method for treating an exon 20 mutant EGFRmediated disorder in a subject, the method comprising administering atherapeutically effective amount of a compound or pharmaceuticalcomposition described herein to a subject.

Some embodiments provide a method for treating an exon 20 mutant HER2mediated disorder in a subject, the method comprising administering atherapeutically effective amount of a compound or pharmaceuticalcomposition described herein to a subject.

Some embodiments provide a use of a compound or a pharmaceuticalcomposition described herein for the treatment of a disease or disorderdescribed herein in a subject.

Some embodiments provide a use of a compound or a pharmaceuticalcomposition described herein for the treatment of an exon 20 mutant EGFRdisorder in a subject.

Some embodiments provide a use of a compound or a pharmaceuticalcomposition described herein for the treatment of an exon 20 mutant HER2disorder in a subject.

Some embodiments provide a use of a compound or a pharmaceuticalcomposition described herein in the manufacture of a medicament for thetreatment of a disease or disorder described herein in a subject.

Some embodiments provide use of a compound or a pharmaceuticalcomposition described herein in the manufacture of a medicament for thetreatment of an exon 20 mutant EGFR mediated disorder in a subject.

Some embodiments provide a use of a compound or a pharmaceuticalcomposition described herein in the manufacture of a medicament for thetreatment of an exon 20 mutant HER2 mediated disorder in a subject.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.In case of conflict, the present application, including any definitionsherein, will control.

DESCRIPTION

One embodiment herein provides compounds, and their pharmaceuticallyacceptable forms, including, but not limited to, salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivativesthereof.

Another embodiment herein provides methods of treating and/or managingvarious diseases and disorders, which comprises administering to apatient a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable form (e.g., salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof. Non-limiting examples of diseases and disorders are describedherein.

Another embodiment herein provides methods of preventing variousdiseases and disorders, which comprises administering to a patient inneed of such prevention a prophylactically effective amount of acompound provided herein, or a pharmaceutically acceptable form (e.g.,salts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof. Non-limiting examples of diseases and disordersare described herein.

In other embodiments, a compound provided herein, or a pharmaceuticallyacceptable form (e.g., salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives) thereof, can be administered incombination with another drug (“second active agent”) or treatment.Second active agents include small molecules and large molecules (e.g.,proteins and antibodies), non-limiting examples of which are providedherein, as well as stem cells. Other methods or therapies that can beused in combination with the administration of compounds provided hereininclude, but are not limited to, surgery, blood transfusions,immunotherapy, biological therapy, radiation therapy, and other non-drugbased therapies presently used to treat, prevent or manage variousdisorders described herein.

Also provided herein are pharmaceutical compositions (e.g., single unitdosage forms) that can be used in the methods provided herein. In oneembodiment, pharmaceutical compositions comprise a compound providedherein, or a pharmaceutically acceptable form (e.g., salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, and optionally one or more second active agents.

While specific embodiments have been discussed, the specification isillustrative only and not restrictive. Many variations of thisdisclosure will become apparent to those skilled in the art upon reviewof this specification.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this specification pertains.

Definitions

As used in the specification and claims, the singular form “a”, “an” and“the” includes plural references unless the context dearly dictatesotherwise.

As used herein, “agent” or “biologically active agent” or “second activeagent” refers to a biological, pharmaceutical, or chemical compound orother moiety. Non-limiting examples include simple or complex organic orinorganic molecules, a peptide, a protein, an oligonucleotide, anantibody, an antibody derivative, an antibody fragment, a vitamin, avitamin derivative, a carbohydrate, a toxin, or a chemotherapeuticcompound, and metabolites thereof. Various compounds can be synthesized,for example, small molecules and oligomers (e.g., oligopeptides andoligonucleotides), and synthetic organic compounds based on various corestructures. In addition, various natural sources can provide activecompounds, such as plant or animal extracts, and the like. A skilledartisan can readily recognize that there is no limit as to thestructural nature of the agents of this disclosure.

The terms “antagonist” and “inhibitor” are used interchangeably, andthey refer to a compound or agent having the ability to inhibit abiological function of a target protein or polypeptide, such as byinhibiting the activity or expression of the target protein orpolypeptide. Accordingly, the terms “antagonist” and “inhibitor” aredefined in the context of the biological role of the target protein orpolypeptide. While some antagonists herein specifically interact with(e.g., bind to) the target, compounds that inhibit a biological activityof the target protein or polypeptide by interacting with other membersof the signal transduction pathway of that target protein or polypeptideare also specifically included within this definition. Non-limitingexamples of biological activity inhibited by an antagonist include thoseassociated with the development, growth, or spread of a tumor, or anundesired immune response as manifested in autoimmune disease.

An “anti-cancer agent”, “anti-tumor agent” or“chemotherapeutic agent”refers to any agent useful in the treatment of a neoplastic condition.One class of anti-cancer agents comprises chemotherapeutic agents.“Chemotherapy” means the administration of one or more chemotherapeuticdrugs and/or other agents to a cancer patient by various methods,including intravenous, oral, intramuscular, intraperitoneal,intravesical, subcutaneous, transdermal, buccal, or inhalation or in theform of a suppository.

The term “cell proliferation” refers to a phenomenon by which the cellnumber has changed as a result of cell division. This term alsoencompasses cell growth by which the cell morphology has changed (e.g.,increased in size) consistent with a proliferative signal.

“Administration” of a disclosed compound encompasses the delivery to asubject of a compound as described herein, or a prodrug or otherpharmaceutically acceptable derivative thereof, using any suitableformulation or route of administration, as discussed herein.

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompassesadministration of two or more agents to the subject so that both agentsand/or their metabolites are present in the subject at the same time.Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound or pharmaceutical composition describedherein that is sufficient to effect the intended application including,but not limited to, disease treatment, as illustrated below. In someembodiments, the amount is that effective for detectable killing orinhibition of the growth or spread of cancer cells; the size or numberof tumors; or other measure of the level, stage, progression or severityof the cancer. The therapeutically effective amount can vary dependingupon the intended application (in vitro or in vivo), or the subject anddisease condition being treated, e.g., the weight and age of thesubject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that willinduce a particular response in target cells, e.g., reduction of cellmigration. The specific dose will vary depending on, for example, theparticular compounds chosen, the species of subject and theirage/existing health conditions or risk for health conditions, the dosingregimen to be followed, the severity of the disease, whether it isadministered in combination with other agents, timing of administration,the tissue to which it is administered, and the physical delivery systemin which it is carried.

As used herein, the terms “treatment”, “treating”, “palliating”“managing” and “ameliorating” are used interchangeably herein. Theseterms refer to an approach for obtaining beneficial or desired resultsincluding, but not limited to, therapeutic benefit and/or a prophylacticbenefit. By therapeutic benefit is meant eradication or amelioration ofthe underlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient can still be afflicted with the underlying disorder. Forprophylactic benefit, the pharmaceutical compounds and/or compositionscan be administered to a patient at risk of developing a particulardisease, or to a patient reporting one or more of the physiologicalsymptoms of a disease, even though a diagnosis of this disease may nothave been made.

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof.

“Signal transduction” is a process during which stimulatory orinhibitory signals are transmitted into and within a cell to elicit anintracellular response. A“modulator” of a signal transduction pathwayrefers to a compound which modulates the activity of one or morecellular proteins mapped to the same specific signal transductionpathway. A modulator can augment (agonist) or suppress (antagonist) theactivity of a signaling molecule.

The term “selective inhibition” or “selectively inhibit” as applied to abiologically active agent refers to the agent's ability to selectivelyreduce the target signaling activity as compared to off-target signalingactivity, via direct or interact interaction with the target. Forexample, a compound that selectively inhibits exon 20 mutant EGFR overwild-type EGFR has an activity of at least about 2× against the mutatedEGF relative to the compound's activity against the wild-type EGFRisoform (e.g., at least about 3×, about 5×, about 10×, about 20×, about50×, or about 100×).

“Radiation therapy” means exposing a patient, using routine methods andcompositions known to the practitioner, to radiation emitters such as,but not limited to, alpha-particle emitting radionuclides (e.g.,actinium and thorium radionuclides), low linear energy transfer (LET)radiation emitters (i.e., beta emitters), conversion electron emitters(e.g., strontium-89 and samarium-153-EDTMP), or high-energy radiation,including without limitation x-rays, gamma rays, and neutrons.

“Subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g., infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or otherprimates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, includingcommercially relevant mammals such as cattle, pigs, horses, sheep,goats, cats, and/or dogs; and/or birds, including commercially relevantbirds such as chickens, ducks, geese, quail, and/or turkeys.

The term “in vivo” refers to an event that takes place in a subject'sbody. In vivo also includes events occurring in rodents, such as rats,mice, guinea pigs, and the like.

The term “in vitro” refers to an event that takes places outside of asubject's body. For example, an in vitro assay encompasses any assayconducted outside of a subject. In vitro assays encompass cell-basedassays in which cells, alive or dead, are employed. In vitro assays alsoencompass a cell-free assay in which no intact cells are employed.

As used herein, “pharmaceutically acceptable derivative” denotes anypharmaceutically acceptable salt, ester, enol ether, or salt of suchester, of such compound, or any other adduct or derivative which, uponadministration to a subject, is capable of providing (directly orindirectly) a compound as otherwise described herein, or a metabolite orresidue (MW about >300) thereof.

As used herein, “pharmaceutically acceptable ester” refers to esterswhich hydrolyze in vivo and include those that break down readily in thehuman body to leave the parent compound or a salt thereof. Such esterscan act as a prodrug as defined herein. Pharmaceutically acceptableesters include, but are not limited to, alkyl, alkenyl, alkynyl, aryl,aralkyl, and cycloalkyl esters of acidic groups, including, but notlimited to, carboxylic acids, phosphoric acids, phosphinic acids,sulfinic acids, sulfonic acids and boronic acids. Examples of estersinclude formates, acetates, propionates, butyrates, acrylates andethylsuccinates. The esters can be formed with a hydroxyl or carboxylicacid group of the parent compound.

As used herein, “pharmaceutically acceptable enol ethers” include, butare not limited to, derivatives of formula —C═C(OR) where R can beselected from alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl.Pharmaceutically acceptable enol esters include, but are not limited to,derivatives of formula —C═C(OC(O)R) where R can be selected fromhydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl and cycloalkyl.

As used herein, a “pharmaceutically acceptable form” of a disclosedcompound includes, but is not limited to, pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives of disclosed compounds. In one embodiment, a“pharmaceutically acceptable form” includes, but is not limited to,pharmaceutically acceptable salts, isomers, prodrugs and isotopicallylabeled derivatives of disclosed compounds. In some embodiments, a“pharmaceutically acceptable form” includes, but is not limited to,pharmaceutically acceptable salts, stereoisomers, prodrugs andisotopically labeled derivatives of disclosed compounds.

In certain embodiments, the pharmaceutically acceptable form is apharmaceutically acceptable salt. As used herein, the term“pharmaceutically acceptable salt” refers to those salts which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of subjects without undue toxicity, irritation,allergic response and the like, and are commensurate with a reasonablebenefit/risk ratio. Pharmaceutically acceptable salts are well known inthe art. For example, Berge et al. describes pharmaceutically acceptablesalts in detail in J. Pharmaceutical Sciences (1977) 66:1-19.Pharmaceutically acceptable salts of the compounds provided hereininclude those derived from suitable inorganic and organic acids andbases. Examples of pharmaceutically acceptable, nontoxic acid additionsalts are salts of an amino group formed with inorganic acids such ashydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid andperchloric acid or with organic acids such as acetic acid, oxalic acid,maleic acid, tartaric acid, citric acid, succinic acid or malonic acidor by using other methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, besylate, benzoate, bisulfate, borate,butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. In some embodiments, organic acids from which salts can bederived include, for example, acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, lactic acid, trifluoracetic acid,maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid,citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonicacid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, andthe like.

The salts can be prepared in situ during the isolation and purificationof the disclosed compounds, or separately, such as by reacting the freebase or free acid of a parent compound with a suitable base or acid,respectively. Pharmaceutically acceptable salts derived from appropriatebases include alkali metal, alkaline earth metal, ammonium andN⁺(C₁₋₄alkyl)⁴ salts. Representative alkali or alkaline earth metalsalts include sodium, lithium, potassium, calcium, magnesium, iron,zinc, copper, manganese, aluminum, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate and aryl sulfonate. Organic bases fromwhich salts can be derived include, for example, primary, secondary, andtertiary amines, substituted amines, including naturally occurringsubstituted amines, cyclic amines, basic ion exchange resins, and thelike, such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, and ethanolamine. In some embodiments,the pharmaceutically acceptable base addition salt can be chosen fromammonium, potassium, sodium, calcium, and magnesium salts.

In certain embodiments, the pharmaceutically acceptable form is a“solvate” (e.g., a hydrate). As used herein, the term “solvate” refersto compounds that further include a stoichiometric or non-stoichiometricamount of solvent bound by non-covalent intermolecular forces. Thesolvate can be of a disclosed compound or a pharmaceutically acceptablesalt thereof. Where the solvent is water, the solvate is a “hydrate”.Pharmaceutically acceptable solvates and hydrates are complexes that,for example, can include 1 to about 100, or 1 to about 10, or 1 to about2, about 3 or about 4, solvent or water molecules. It will be understoodthat the term “compound” as used herein encompasses the compound andsolvates of the compound, as well as mixtures thereof.

In certain embodiments, the pharmaceutically acceptable form is aprodrug. As used herein, the term “prodrug” refers to compounds that aretransformed in vivo to yield a disclosed compound or a pharmaceuticallyacceptable form of the compound. A prodrug can be inactive whenadministered to a subject, but is converted in vivo to an activecompound, for example, by hydrolysis (e.g., hydrolysis in blood). Incertain cases, a prodrug has improved physical and/or deliveryproperties over the parent compound. Prodrugs can increase thebioavailability of the compound when administered to a subject (e.g., bypermitting enhanced absorption into the blood following oraladministration) or which enhance delivery to a biological compartment ofinterest (e.g., the brain or lymphatic system) relative to the parentcompound. Exemplary prodrugs include derivatives of a disclosed compoundwith enhanced aqueous solubility or active transport through the gutmembrane, relative to the parent compound.

The prodrug compound often offers advantages of solubility, tissuecompatibility or delayed release in a mammalian organism (see, e.g.,Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier,Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al.,“Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14,and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche,American Pharmaceutical Association and Pergamon Press, 1987, both ofwhich are incorporated in full by reference herein. Exemplary advantagesof a prodrug can include, but are not limited to, its physicalproperties, such as enhanced water solubility for parenteraladministration at physiological pH compared to the parent compound, orit can enhance absorption from the digestive tract, or it can enhancedrug stability for long-term storage.

The term “prodrug” is also meant to include any covalently bondedcarriers, which release the active compound in vivo when such prodrug isadministered to a subject. Prodrugs of an active compound, as describedherein, can be prepared by modifying functional groups present in theactive compound in such a way that the modifications are cleaved, eitherin routine manipulation or in vivo, to the parent active compound.Prodrugs include compounds wherein a hydroxy, amino or mercapto group isbonded to any group that, when the prodrug of the active compound isadministered to a subject, cleaves to form a free hydroxy, free amino orfree mercapto group, respectively. Examples of prodrugs include, but arenot limited to, acetate, formate and benzoate derivatives of an alcoholor acetamide, formamide and benzamide derivatives of an amine functionalgroup in the active compound and the like. Other examples of prodrugsinclude compounds that comprise —NO, —NO₂, —ONO, or —ONO₂ moieties.Prodrugs can typically be prepared using well known methods, such asthose described in Burger's Medicinal Chemistry and Drug Discovery,172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995), and Design ofProdrugs (H. Bundgaard ed., Elselvier, New York, 1985).

For example, if a disclosed compound or a pharmaceutically acceptableform of the compound contains a carboxylic acid functional group, aprodrug can comprise a pharmaceutically acceptable ester formed by thereplacement of the hydrogen atom of the acid group with a group such as(C₁-₈)alkyl, (C₁-₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 10 carbon atoms,N-(alkoxycarbonyl) aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁₋₂)alkylamino(C₂₋₃)alkyl (such as [3-dimethylaminoethyl),carbamoyl-(C₁₋₂)alkyl, N,N-di(C₁₋₂)alkylcarbamoyl-(C₁₋₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂₋₃)alkyl.

Similarly, if a disclosed compound or a pharmaceutically acceptable formof the compound contains an alcohol functional group, a prodrug can beformed by the replacement of the hydrogen atom of the alcohol group witha group such as (C₁₋₆)alkanoyloxymethyl, 1-((C₁₋₆)alkanoyloxy)ethyl,1-methyl-1-((C₁₋₆)alkanoyloxy)ethyl,

(C₁₋₆)alkoxycarbonyloxymethyl, N—(C₁₋₆)alkoxycarbonylaminomethyl,succinoyl,(C₁₋₆)alkanoyl, α-amino(C₁₋₄)alkanoyl, arylacyl, and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, —P(O)(OH)₂,—P(O)(O(C₁₋₆)alkyl)₂ or glycosyl (the radical resulting from the removalof a hydroxyl group of the hemiacetal form of a carbohydrate).

If a disclosed compound or a pharmaceutically acceptable form of thecompound incorporates an amine functional group, a prodrug can be formedby the replacement of a hydrogen atom in the amine group with a groupsuch as R-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ are eachindependently selected from (C₁₋₁₀)alkyl, (C₃₋₇)cycloalkyl, benzyl, anatural α-aminoacyl or natural α-aminoacyl-natural-α-aminoacyl,

—C(OH)C(O)OY¹ wherein Y¹ is H, (C₁₋₆)alkyl or benzyl; —C(OY²)Y³ whereinY² is (C₁₋₄)alkyl and Y³ is (C₁₋₆)alkyl, carboxy(C₁₋₆)alkyl,amino(C₁₋₄)alkyl or mono-N— or di-N,N—(C₁₋₆)alkylaminoalkyl; and—C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵ is mono-N— or di-N—(C₁₆)alkylamino, morpholino, piperidin-1-yl or pyrrolidin-1-yl.

In certain embodiments, the pharmaceutically acceptable form is anisomer. “Isomers” are different compounds that have the same molecularformula. “Stereoisomers” are isomers that differ only in the way theatoms are arranged in space. As used herein, the term “isomer” includesany and all geometric isomers and stereoisomers. For example, “isomers”include geometric double bond cis- and trans-isomers, also termed E- andZ-isomers; R- and S-enantiomers; diastereomers, (d)-isomers and(I)-isomers, racemic mixtures thereof; and other mixtures thereof, asfalling within the scope of this disclosure.

Geometric isomers can be represented by the symbol

which denotes a bond that can be a single, double or triple bond asdescribed herein. Provided herein are various geometric isomers andmixtures thereof resulting from the arrangement of substituents around acarbon-carbon double bond or arrangement of substituents around acarbocyclic ring. Substituents around a carbon-carbon double bond aredesignated as being in the “Z” or “E” configuration wherein the terms“Z” and “E” are used in accordance with IUPAC standards. Unlessotherwise specified, structures depicting double bonds encompass boththe “E” and “Z” isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “is” or “trans,” where“as” represents substituents on thesame side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangement of substituentsaround a carbocyclic ring can also be designated as “cis” or “trans.”The term “cis” represents substituents on the same side of the plane ofthe ring, and the term “trans” represents substituents on opposite sidesof the plane of the ring. Mixtures of compounds wherein the substituentsare disposed on both the same and opposite sides of plane of the ringare designated “cis/trans.”

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A mixture of a pair of enantiomers in anyproportion can be known as a “racemic” mixture. The term “(t)” is usedto designate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R-S system. When a compound is anenantiomer, the stereochemistry at each chiral carbon can be specifiedby either R or S. Resolved compounds whose absolute configuration isunknown can be designated (+) or (−) depending on the direction (dextro-or levorotatory) which they rotate plane polarized light at thewavelength of the sodium D line. Certain of the compounds describedherein contain one or more asymmetric centers and can thus give rise toenantiomers, diastereomers, and other stereoisomeic forms that can bedefined, in terms of absolute stereochemistry at each asymmetric atom,as (R)- or (S)-. The present chemical entities, pharmaceuticalcompositions and methods are meant to include all such possible isomers,including racemic mixtures, optically substantially pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers can beprepared, for example, using chiral synthons or chiral reagents, orresolved using conventional techniques.

The “enantiomeric excess” or “% enantiomeric excess” of a compositioncan be calculated using the equation shown below. In the example shownbelow, a composition contains 90% of one enantiomer, e.g., the Senantiomer, and 10% of the other enantiomer, e.g., the R enantiomer.

ee=(90−10)/100=80%.

Thus, a composition containing 90% of one enantiomer and 10% of theother enantiomer is said to have an enantiomeric excess of 80%. Somecompositions described herein contain an enantiomeric excess of at leastabout 50%, about 75%, about 90%, about 95%, or about 99% of the Senantiomer. In other words, the compositions contain an enantiomericexcess of the S enantiomer over the R enantiomer. In other embodiments,some compositions described herein contain an enantiomeric excess of atleast about 50%, about 75%, about 90%, about 95%, or about 99% of the Renantiomer. In other words, the compositions contain an enantiomericexcess of the R enantiomer over the S enantiomer.

For instance, an isomer/enantiomer can, in some embodiments, be providedsubstantially free of the corresponding enantiomer, and can also bereferred to as “optically enriched,” “enantiomerically enriched,”“enantiomerically pure” and “non-racemic,” as used interchangeablyherein. These terms refer to compositions in which the percent by weightof one enantiomer is greater than the amount of that one enantiomer in acontrol mixture of the racemic composition (e.g., greater than 1:1 byweight). For example, an enantiomerically enriched preparation of the Senantiomer means a preparation of the compound having greater than about50% by weight of the S enantiomer relative to the R enantiomer, such asat least about 75% by weight, further such as at least about 80% byweight. In some embodiments, the enrichment can be much greater thanabout 80% by weight, providing a “substantially enantiomericallyenriched,” “substantially enantiomerically pure” or a “substantiallynon-racemic” preparation, which refers to preparations of compositionswhich have at least about 85% by weight of one enantiomer relative toother enantiomer, such as at least about 90% by weight, and further suchas at least about 95% by weight. In certain embodiments, the compoundprovided herein can be made up of at least about 90% by weight of oneenantiomer. In other embodiments, the compound can be made up of atleast about 95%, about 98%, or about 99% by weight of one enantiomer.

In some embodiments, the compound is a racemic mixture of (S)- and(R)-isomers. In other embodiments, provided herein is a mixture ofcompounds wherein individual compounds of the mixture existpredominately in an (S)- or (R)-isomeric configuration. For example, thecompound mixture has an (S)-enantiomeric excess of greater than about55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%,about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about99.5%, or more. In other embodiments, the compound mixture has an(S)-enantiomeric excess of greater than about 55% to about 99.5%,greater than about 60% to about 99.5%, greater than about 65% to about99.5%, greater than about 70% to about 99.5%, greater than about 75% toabout 99.5%, greater than about 80% to about 99.5%, greater than about85% to about 99.5%, greater than about 90% to about 99.5%, greater thanabout 95% to about 99.5%, greater than about 96% to about 99.5%, greaterthan about 97% to about 99.5%, greater than about 98% to greater thanabout 99.5%, greater than about 99% to about 99.5%, or more. In otherembodiments, the compound mixture has an (R)-enantiomeric purity ofgreater than about 55%, about 60%, about 65%, about 70%, about 75%,about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about98%, about 99%, about 99.5% or more. In some other embodiments, thecompound mixture has an (R)-enantiomeric excess of greater than about55% to about 99.5%, greater than about 60% to about 99.5%, greater thanabout 65% to about 99.5%, greater than about 70% to about 99.5%, greaterthan about 75% to about 99.5%, greater than about 80% to about 99.5%,greater than about 85% to about 99.5%, greater than about 90% to about99.5%, greater than about 95% to about 99.5%, greater than about 96% toabout 99.5%, greater than about 97% to about 99.5%, greater than about98% to greater than about 99.5%, greater than about 99% to about 99.5%or more.

In other embodiments, the compound mixture contains identical chemicalentities except for their stereochemical orientations, namely (S)- or(R)-isomers. For example, if a compound disclosed herein has a —CH(R)—unit, and R is not hydrogen, then the —CH(R)— is in an (S)- or(R)-stereochemical orientation for each of the identical chemicalentities. In some embodiments, the mixture of identical chemicalentities is a racemic mixture of (S)- and (R)-isomers. In anotherembodiment, the mixture of the identical chemical entities (except fortheir stereochemical orientations), contain predominately (S)-isomers orpredominately (R)-isomers. For example, the (S)-isomers in the mixtureof identical chemical entities are present at about 55%, about 60%,about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about95%, about 96%, about 97%, about 98%, about 99%, about 99.5%, or more,relative to the (R)-isomers. In some embodiments, the (S)-isomers in themixture of identical chemical entities are present at an(S)-enantiomeric excess of greater than about 55% to about 99.5%,greater than about 60% to about 99.5%, greater than about 65% to about99.5%, greater than about 70% to about 99.5%, greater than about 75% toabout 99.5%, greater than about 80% to about 99.5%, greater than about85% to about 99.5%, greater than about 90% to about 99.5%, greater thanabout 95% to about 99.5%, greater than about 96% to about 99.5%, greaterthan about 97% to about 99.5%, greater than about 98% to greater thanabout 99.5%, greater than about 99% to about 99.5% or more.

In another embodiment, the (R)-isomers in the mixture of identicalchemical entities (except for their stereochemical orientations), arepresent at about 55%, about 60%, about 65%, about 70%, about 75%, about80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%,about 99%, about 99.5%, or more, relative to the (S)-isomers. In someembodiments, the (R)-isomers in the mixture of identical chemicalentities (except for their stereochemical orientations), are present ata (R)-enantiomeric excess greater than about 55% to about 99.5%, greaterthan about 60% to about 99.5%, greater than about 65% to about 99.5%,greater than about 70% to about 99.5%, greater than about 75% to about99.5%, greater than about 80% to about 99.5%, greater than about 85% toabout 99.5%, greater than about 90% to about 99.5%, greater than about95% to about 99.5%, greater than about 96% to about 99.5%, greater thanabout 97% to about 99.5%, greater than about 98% to greater than about99.5%, greater than about 99% to about 99.5%, or more.

Enantiomers can be isolated from racemic mixtures by any method known tothose skilled in the art, including chiral high pressure liquidchromatography (HPLC), the formation and crystallization of chiralsalts, or prepared by asymmetric syntheses. See, for example,Enantiomers, Racemates and Resolutions (Jacques, Ed., WileyInterscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977);Stereochemistry of Carbon Compounds (E. L. Eliel, Ed., McGraw-Hill, N Y,1962); and Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. EIM, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

Optical isomers can be obtained by resolution of the racemic mixturesaccording to conventional processes, e.g., by formation ofdiastereoisomeric salts, by treatment with an optically active acid orbase. Examples of appropriate acids include, but are not limited to,tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, andcamphorsulfonic acid. The separation of the mixture of diastereoisomersby crystallization followed by liberation of the optically active basesfrom these salts affords separation of the isomers. Another methodinvolves synthesis of covalent diastereoisomeric molecules by reactingdisclosed compounds with an optically pure acid in an activated form oran optically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically enriched compound. Optically active compounds can alsobe obtained by using active starting materials. In some embodiments,these isomers can be in the form of a free acid, a free base, an esteror a salt.

In certain embodiments, the pharmaceutically acceptable form is atautomer. As used herein, the term “tautomer” is a type of isomer thatincludes two or more interconvertible compounds resulting from at leastone formal migration of a hydrogen atom and at least one change invalency (e.g., a single bond to a double bond, a triple bond to a singlebond, or vice versa). “Tautomerization” includes prototropic orproton-shift tautomerization, which is considered a subset of acid-basechemistry. “Prototropic tautomerization” or “proton-shifttautomerization” involves the migration of a proton accompanied bychanges in bond order. The exact ratio of the tautomers depends onseveral factors, including temperature, solvent, and pH. Wheretautomerization is possible (e.g., in solution), a chemical equilibriumof tautomers can be reached. Tautomerizations (i.e., the reactionproviding a tautomeric pair) can be catalyzed by acid or base, or canoccur without the action or presence of an external agent. Exemplarytautomerizations include, but are not limited to, keto-to-enol;amide-to-imide; lactam-to-lactim; enamine-to-imine; and enamine-to-(adifferent) enamine tautomerizations. A specific example of keto-enoltautomerization is the interconversion of pentane-2,4-dione and4-hydroxypent-3-en-2-one tautomers. Another example of tautomerizationis phenol-keto tautomerization. A specific example of phenol-ketotautomerization is the interconversion of pyridin-4-ol andpyridin-4(1H)-one tautomers.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this disclosure.

The disclosure also embraces pharmaceutically acceptable forms that are“isotopically labeled derivatives” which are compounds that areidentical to those recited herein, except that one or more atoms arereplaced by an atom having an atomic mass or mass number different fromthe atomic mass or mass number usually found in nature. Examples ofisotopes that can be incorporated into disclosed compounds includeisotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine andchlorine, such as ²H, ³H, ¹³C ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F,and ³⁶Cl, respectively. Certain isotopically-labeled disclosed compounds(e.g., those labeled with ³H and ¹⁴C) are useful in compound and/orsubstrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14(i.e., ¹⁴C) isotopes can allow for ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) can afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements). Isotopically labeled disclosed compoundscan generally be prepared by substituting an isotopically labeledreagent for a non-isotopically labeled reagent. In some embodiments,provided herein are compounds that can also contain unnaturalproportions of atomic isotopes at one or more of atoms that constitutesuch compounds. All isotopic variations of the compounds as disclosedherein, whether radioactive or not, are encompassed within the scope ofthe present disclosure. In some embodiments, radiolabeled compounds areuseful for studying metabolism and/or tissue distribution of thecompounds or to alter the rate or path of metabolism or other aspects ofbiological functioning

“Pharmaceutically acceptable carrier” or “pharmaceutically acceptableexcipient” includes any and all solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents and the like. The pharmaceutically acceptable carrier orexcipient does not destroy the pharmacological activity of the disclosedcompound and is nontoxic when administered in doses sufficient todeliver a therapeutic amount of the compound. The use of such media andagents for pharmaceutically active substances is well known in the art.Except insofar as any conventional media or agent is incompatible withthe active ingredient, its use in the therapeutic compositions asdisclosed herein is contemplated. Non-limiting examples ofpharmaceutically acceptable carriers and excipients include sugars suchas lactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; cocoa butter and suppository waxes; oils such aspeanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, cornoil and soybean oil; glycols, such as polyethylene glycol and propyleneglycol; esters such as ethyl oleate and ethyl laurate; agar; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffersolutions; non-toxic compatible lubricants such as sodium lauryl sulfateand magnesium stearate; coloring agents; releasing agents; coatingagents; sweetening, flavoring and perfuming agents; preservatives;antioxidants; ion exchangers; alumina; aluminum stearate; lecithin;selfemulsifying drug delivery systems (SEDDS) such as d-atocopherolpolyethyleneglycol 1000 succinate; surfactants used in pharmaceuticaldosage forms such as Tweens or other similar polymeric deliverymatrices; serum proteins such as human serum albumin; glycine; sorbicacid; potassium sorbate; partial glyceride mixtures of saturatedvegetable fatty acids; water, salts or electrolytes such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, and zinc salts; colloidal silica; magnesiumtrisilicate; polyvinyl pyrrolidone; cellulose-based substances;polyacrylates; waxes; and polyethylene-polyoxypropylene-block polymers.Cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modifiedderivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-cyclodextrins, or other solubilized derivatives can alsobe used to enhance delivery of compounds described herein.

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75th ed., inside cover, and specificfunctional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry, Thomas Sorrell, University Science Books, Sansalito, 1999;Smith and March March's Advanced Organic Chemistry, 5th ed., John Wiley& Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3rd ed., Cambridge UniversityPress, Cambridge, 1987.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to ten carbon atoms (e.g., C₁₋₁₀ alkyl).Whenever it appears herein, a numerical range such as “1 to 10” refersto each integer in the given range; e.g., “1 to 10 carbon atoms” meansthat the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3carbon atoms, etc., up to and including 10 carbon atoms, although thepresent definition also covers the occurrence of the term “alkyl” whereno numerical range is designated. In some embodiments, “alkyl” can be aC₁₋₆ alkyl group. In some embodiments, alkyl groups have 1 to 10, 1 to8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated straightchain alkyls include, but are not limited to, -methyl, -ethyl,-n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branchedalkyls include, but are not limited to, -isopropyl, -sec-butyl,-isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl,2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl,3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, and thelike. The alkyl is attached to the parent molecule by a single bond.Unless stated otherwise in the specification, an alkyl group isoptionally substituted by one or more of substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)N(R^(a))₂ (where t is 1 or 2), —P(═O)(R^(a))(R^(a)), or—O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen, alkyl,haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein. In a non-limiting embodiment, a substituted alkyl can beselected from fluoromethyl, difluoromethyl, trifluoromethyl,2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl,3-hydroxypropyl, benzyl, and phenethyl.

“Perhaloalkyl” refers to an alkyl group in which all of the hydrogenatoms have been replaced with a halogen selected from fluoro, chloro,bromo, and iodo. In some embodiments, all of the hydrogen atoms are eachreplaced with fluoro. In some embodiments, all of the hydrogen atoms areeach replaced with chloro. Examples of perhaloalkyl groups include —CF₃,—CF₂CF₃, —CF₂CF₂CF₃, —CFCl₂, —CF₂Cl and the like.

“Alkyl-cycloalkyl” refers to an -(alkyl)cycloalkyl radical where alkyland cycloalkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for alkyl and cycloalkyl respectively. The“alkyl-cycloalkyl” is bonded to the parent molecular structure throughthe alkyl group. The terms “alkenyl-cycloalkyl” and“alkynyl-cycloalkyl”mirror the above description of“alkyl cycloalkyl”wherein the term “alkyl” is replaced with “alkenyl” or “alkynyl”respectively, and “alkenyl” or “alkynyl” are as described herein.

“Alkyl-aryl” refers to an -(alkyl)aryl radical where aryl and alkyl areas disclosed herein and which are optionally substituted by one or moreof the substituents described as suitable substituents for aryl andalkyl respectively. The “alkylaryl” is bonded to the parent molecularstructure through the alkyl group. The terms “-(alkenyl)aryl” and“-(alkynyl)aryl” mirror the above description of “-(alkyl)aryl” whereinthe term “alkyl” is replaced with “alkenyl” or “alkynyl” respectively,and “alkenyl” or “alkynyl” are as described herein.

“Alkyl-heteroaryl” refers to an -(alkyl)heteroaryl radical whereheteroaryl and alkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroaryl and alkyl respectively. The “alkylheteroaryl” is bonded to the parent molecular structure through thealkyl group. The terms “-(alkenyl)heteroaryl” and “-(alkynyl)heteroaryl”mirror the above description of “(alkyl) heteroaryl” wherein the term“alkyl” is replaced with “alkenyl” or “alkynyl” respectively, and“alkenyl” or “alkynyl” are as described herein.

“Alkyl-heterocyclyl” refers to an -(alkyl)heterocycyl radical wherealkyl and heterocyclyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heterocyclyl and alkyl respectively. The“alkyl-heterocyclyl” is bonded to the parent molecular structure throughthe alkyl group. The terms “-(alkenyl)heterocyclyl” and“-(alkynyl)heterocyclyl” mirror the above description of“-(alkyl)heterocycyl” wherein the term“alkyl” is replaced with“alkenyl”or “alkynyl” respectively, and “alkenyl” or “alkynyl” are as describedherein.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, and having from two to ten carbon atoms (i.e.,C₂₋₁₀ alkenyl). Whenever it appears herein, a numerical range such as “2to 10” refers to each integer in the given range; e.g., “2 to 10 carbonatoms” means that the alkenyl group can consist of 2 carbon atoms, 3carbon atoms, etc., up to and including 10 carbon atoms. In certainembodiments, an alkenyl comprises two to eight carbon atoms. In otherembodiments, an alkenyl comprises two to six carbon atoms (e.g., C₂₋₆alkenyl). The alkenyl is attached to the parent molecular structure by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. The oneor more carbon-carbon double bonds can be internal (such as in2-butenyl) or terminal (such as in 1-butenyl). Examples of C₂₋₄ alkenylgroups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl(C₄), 2-butenyl (C₄), 2-methylprop-2-enyl (C₄), butadienyl (C₄) and thelike. Examples of C₂₋₄ alkenyl groups include the aforementioned C₂₋₄alkenyl groups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆),2,3-dimethyl-2-butenyl (C₆) and the like. Additional examples of alkenylinclude heptenyl (C₇), octenyl (C₈), octatrienyl (C₈) and the like.Unless stated otherwise in the specification, an alkenyl group can beoptionally substituted by one or more substituents which independentlyinclude: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl,aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)N(R^(a))₂ (where t is 1 or 2), —P(═O)(R^(a))(R^(a)), or—O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen, alkyl,haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, having from two to ten carbon atoms (i.e., C₂10alkynyl). Whenever it appears herein, a numerical range such as “2 to10” refers to each integer in the given range; e.g., “2 to 10 carbonatoms” means that the alkynyl group can consist of 2 carbon atoms, 3carbon atoms, etc., up to and including 10 carbon atoms. In certainembodiments, an alkynyl comprises two to eight carbon atoms. In otherembodiments, an alkynyl has two to six carbon atoms (e.g., C₂₋₆alkynyl). The alkynyl is attached to the parent molecular structure by asingle bond, for example, ethynyl, propynyl, butynyl, pentynyl,3-methyl-4-pentenyl, hexynyl, and the like. Unless stated otherwise inthe specification, an alkynyl group can be optionally substituted by oneor more substituents which independently include: acyl, alkyl, alkenyl,alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino,amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R)₂, —N(R^(a))S(O)_(t)N(R^(a))₂ (where t is 1 or 2),—P(═O)(R^(a))(R^(a)), or —O—P(═O)(OR^(a))₂ where each R^(a) isindependently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl,aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl, and each of these moieties can be optionallysubstituted as defined herein.

“Alkoxy” refers to the group —O-alkyl, including from 1 to 10 carbonatoms of a straight, branched, saturated cyclic configuration andcombinations thereof, attached to the parent molecular structure throughan oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy,butoxy, t-butoxy, pentoxy, cyclopropyloxy, cyclohexyloxy and the like.“Lower alkoxy” refers to alkoxy groups containing one to six carbons. Insome embodiments, C₁₋₄ alkoxy is an alkoxy group which encompasses bothstraight and branched chain alkyls of from 1 to 4 carbon atoms. Unlessstated otherwise in the specification, an alkoxy group can be optionallysubstituted by one or more substituents which independently include:acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl,aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)N(R^(a))₂ (where t is 1 or 2), —P(═O)(R^(a))(R^(a)), or—O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen, alkyl,haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein. The terms “alkenoxy” and “alkynoxy” mirror the above descriptionof “alkoxy” wherein the prefix “alk” is replaced with “alken” or “alkyn”respectively, and the parent “alkenyl” or “alkynyl” terms are asdescribed herein.

The term “alkoxycarbonyl” refers to a group of the formula(alkoxy)(C═O)— attached to the parent molecular structure through thecarbonyl carbon having from 1 to 10 carbon atoms. Thus, a C₁₋₆alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atomsattached through its oxygen to a carbonyl linker. The C₁₋₆ designationdoes not include the carbonyl carbon in the atom count. “Loweralkoxycarbonyl” refers to an alkoxycarbonyl group wherein the alkylportion of the alkoxy group is a lower alkyl group. In some embodiments,C₁₋₄ alkoxy is an alkoxy group which encompasses both straight andbranched chain alkoxy groups of from 1 to 4 carbon atoms. Unless statedotherwise in the specification, an alkoxycarbonyl group can beoptionally substituted by one or more substituents which independentlyinclude: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl,aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)N(R^(a))₂ (where t is 1 or 2), —P(═O)(R^(a))(R^(a)), or—O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen, alkyl,haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein. The terms “alkenoxycarbonyl” and “alkynoxycarbonyl” mirror theabove description o“alkoxycarbonyl” wherein the prefix “alk” is replacedwith “alken” or “alkyn” respectively, and the parent “alkenyl” or“alkynyl” terms are as described herein.

“Acyl” refers to R—C(O)— groups such as, but not limited to,(alkyl)-C(O)—, (alkenyl)-C(O)—, (alkynyl)-C(O)—, (aryl)-C(O)—,(cycloalkyl)-C(O)—, (heteroaryl)-C(O)—, (heteroalkyl)-C(O)—, and(heterocycloalkyl)-C(O)—, wherein the group is attached to the parentmolecular structure through the carbonyl functionality. In someembodiments, it is a C₁₋₁₀ acyl radical which refers to the total numberof chain or ring atoms of the, for example, alkyl, alkenyl, alkynyl,aryl, cyclohexyl, heteroaryl or heterocycloalkyl portion plus thecarbonyl carbon of acyl. For example, a C₄-acyl has three other ring orchain atoms plus carbonyl. If the R radical is heteroaryl orheterocycloalkyl, the hetero ring or chain atoms contribute to the totalnumber of chain or ring atoms. Unless stated otherwise in thespecification, the “R” of an acyloxy group can be optionally substitutedby one or more substituents which independently include: acyl, alkyl,alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy,amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R_(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)N(R^(a))₂ (where t is 1 or2), —P(═O)(R^(a))(R^(a)), or —O—P(═O)(OR^(a))₂ where each R^(a) isindependently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl,aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl, and each of these moieties can be optionallysubstituted as defined herein.

“Acyloxy” refers to a R(C═O)O— radical wherein “R” can be alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl,cyclohexyl, heteroaryl or heterocycloalkyl, which are as describedherein. The acyloxy group is attached to the parent molecular structurethrough the oxygen functionality. In some embodiments, an acyloxy groupis a C₁₋₄ acyloxy radical which refers to the total number of chain orring atoms of the alkyl, alkenyl, alkynyl, aryl, cyclohexyl, heteroarylor heterocycloalkyl portion of the acyloxy group plus the carbonylcarbon of acyl, i.e., a C₄-acyloxy has three other ring or chain atomsplus carbonyl. If the R radical is heteroaryl or heterocycloalkyl, thehetero ring or chain atoms contribute to the total number of chain orring atoms. Unless stated otherwise in the specification, the “R” of anacyloxy group can be optionally substituted by one or more substituentswhich independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy,alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino,imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R⁸)C(O)N(R⁸)₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)N(R^(a))₂ (where t is 1 or 2), —P(═O)(R^(a))(R^(a)), or—O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen, alkyl,haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Amino” or “amine” refers to a —N(R^(b))₂, —N(R^(b))—R^(b)—, or—R^(b)N(R^(b))R^(b)— radical group, where each R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon) orheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.When a —N(R^(b))₂ group has two R^(b) other than hydrogen, they can becombined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-memberedring. For example, —N(R^(b)), is meant to include, but not be limitedto, 1-pyrrolidinyl and 4-morpholinyl. Unless stated otherwise in thespecification, an amino group can be optionally substituted by one ormore substituents which independently include: acyl, alkyl, alkenyl,alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino,amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R_(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)N(R^(a))₂ (where t is 1 or2), —P(═O)(R^(a))(R^(a)), or —O—P(═O)(OR^(a))₂ where each R^(a) isindependently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl,aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl, and each of these moieties can be optionallysubstituted as defined herein.

The terms “amine” and “amino” also refer to N-oxides of the groups—N⁺(H)(R^(a))O—, and —N⁺(R^(a))(R^(a))O—, R^(a) as described above,where the N-oxide is bonded to the parent molecular structure throughthe N atom. N-oxides can be prepared by treatment of the correspondingamino group with, for example, hydrogen peroxide orm-chloroperoxybenzoic acid. The person skilled in the art is familiarwith reaction conditions for carrying out the N-oxidation.

“Amide” or “amido” refers to a chemical moiety with formula—C(O)N(R^(b))₂, —C(O)N(R^(b))—, —NR_(b)C(O)R_(b), or —NR_(b)C(O)— whereR_(b) is independently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, this radical is a C₁₋₄ amidoor amide radical, which includes the amide carbonyl in the total numberof carbons in the radical. When a —C(O)N(R^(b))₂ has two R^(b) otherthan hydrogen, they can be combined with the nitrogen atom to form a 3-,4-, 5-, 6-, or 7-membered ring. For example, N(R^(b))₂ portion of a—C(O)N(R^(b)), radical is meant to include, but not be limited to,1-pyrrolidinyl and 4-morpholinyl. Unless stated otherwise in thespecification, an amido R^(b) group can be optionally substituted by oneor more substituents which independently include: acyl, alkyl, alkenyl,alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino,amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)N(R^(a))₂ (where t is 1 or2), —P(═O)(R^(a))(R^(a)), or —O—P(═O)(OR^(a))₂ where each R^(a) isindependently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl,aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl, and each of these moieties can be optionallysubstituted as defined herein.

The term “amide” or “amido” is inclusive of an amino acid or a peptidemolecule. Any amine, hydroxy, or carboxyl side chain on the compoundsdescribed herein can be transformed into an amide group. The proceduresand specific groups to make such amides are known to those of skill inthe art and can readily be found in reference sources such as Greene andWuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley &Sons, New York, N.Y., 1999, which is incorporated herein by reference inits entirety.

“Amidino” refers to both the —C(═NR^(b))N(R^(b)), and—N(R^(b))—C(═NR^(b))— radicals, where each R^(b) is independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl(bonded through a chain carbon), cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocycloalkyl (bonded through a ring carbon),heterocycloalkylalkyl, heteroaryl (bonded through a ring carbon) orheteroarylalkyl, unless stated otherwise in the specification, each ofwhich moiety can itself be optionally substituted as described herein.

“Aromatic” or “aryl” refers to a radical with 6 to 14 ring atoms (e.g.,C₆₋₁₄ aromatic or C₆₋₁₄ aryl) which has at least one ring having aconjugated pi electron system which is carbocyclic (e.g., phenyl,fluorenyl, and naphthyl). In some embodiments, the aryl is a C₆₋₁₀ arylgroup. For example, bivalent radicals formed from substituted benzenederivatives and having the free valences at ring atoms are named assubstituted phenylene radicals. In other embodiments, bivalent radicalsderived from univalent polycyclic hydrocarbon radicals whose names endin “-yl” by removal of one hydrogen atom from the carbon atom with thefree valence are named by adding “-idene” to the name of thecorresponding univalent radical, e.g., a naphthyl group with two pointsof attachment is termed naphthylidene. Whenever it appears herein, anumerical range such as “6 to 14 aryl” refers to each integer in thegiven range; e.g., “6 to 14 ring atoms” means that the aryl group canconsist of 6 ring atoms, 7 ring atoms, etc., up to and including 14 ringatoms. The term includes monocyclic or fused-ring polycyclic (i.e.,rings which share adjacent pairs of ring atoms) groups. Polycyclic arylgroups include bicycles, tricycles, tetracycles, and the like. In amulti-ring group, only one ring is required to be aromatic, so groupssuch as indanyl are encompassed by the aryl definition. Non-limitingexamples of aryl groups include phenyl, phenalenyl, naphthalenyl,tetrahydronaphthyl, phenanthrenyl, anthracenyl, fluorenyl, indolyl,indanyl, and the like. Unless stated otherwise in the specification, anaryl moiety can be optionally substituted by one or more substituentswhich independently include: acyl, alkyl, alkenyl, alkynyl, alkoxy,alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino,imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)N(R^(a))₂ (where t is 1 or 2), —P(═O)(R^(a))(R^(a)), or—O—P(═O(OR^(a))₂ where each R^(a) is independently hydrogen, alkyl,haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Aryloxy” refers to the group —O-aryl, including from 6 to 14 carbonatoms of an aromatic configuration and combinations thereof, attached tothe parent molecular structure through an oxygen. Aryl is as describedherein. Examples include phenoxy, phenalenyloxy, naphthalenyloxy,tetrahydronaphthyloxy, phenanthrenyloxy, anthracenyloxy, fluorenyloxy,indolyloxy, indanyloxy and the like. “Lower aryloxy” refers to aryloxygroups containing 6 to 10 carbons. Unless stated otherwise in thespecification, an alkoxy group can be optionally substituted by one ormore substituents which independently include: acyl, alkyl, alkenyl,alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino,amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)N(R^(a))₂ (where t is 1 or2), —P(═O)(R^(a))(R^(a)), or —O—P(═O)(OR^(a))₂ where each R^(a) isindependently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl,aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl, and each of these moieties can be optionallysubstituted as defined herein. The terms “alkenoxy” and “alkynoxy”mirror the above description of “alkoxy” wherein the prefix “alk” isreplaced with “alken” or “alkyn” respectively, and the parent “alkenyl”or “alkynyl” terms are as described herein.

“Aralkyl” or “arylalkyl” refers to an -(alkyl)aryl radical where aryland alkyl are as disclosed herein and which are optionally substitutedby one or more of the substituents described as suitable substituentsfor aryl and alkyl respectively. The “aralkyl/arylalkyl” is bonded tothe parent molecular structure through the alkyl group. The terms“aralkenyl/arylalkenyl” and “aralkynyl/arylalkynyl” mirror the abovedescription of “aralkyl/arylalkyl” wherein the “alkyl” is replaced with“alkenyl” or “alkynyl” respectively, and the “alkenyl” or “alkynyl”terms are as described herein.

“Carbamate” refers to any of the following radicals: —O—(C═O)—N(R^(b))—,—O—(C═O)—N(R^(b))₂, —N(R^(b))—(C═O)—O—, and —N(R^(b))—(C═O)—OR^(b),wherein each R^(b) is independently selected from alkyl, alkenylalkynyl, haloalkyl, heteroalkyl (bonded through a chain carbon),cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bondedthrough a ring carbon), heterocycloalkylalkyl, heteroaryl (bondedthrough a ring carbon) or heteroarylalkyl, unless stated otherwise inthe specification, each of which moiety can itself be optionallysubstituted as described herein.

“Carbonate” refers to a —(C═O)—O— radical.

“Carbonyl” refers to a —(C═O)— radical.

“Carboxaldehyde” refers to a —(C═O)H radical.

“Carboxyl” refers to a —(C═O)OH radical.

“Cyano” refers to a —CN radical.

“Cycloalkyl” and “carbocyclyl” each refer to a monocyclic or polycyclicradical that contains only carbon and hydrogen, and can be saturated orpartially unsaturated. Partially unsaturated cycloalkyl groups can betermed “cycloalkenyl” if the carbocycle contains at least one doublebond, or “cycloalkynyl” if the carbocycle contains at least one triplebond. Cycloalkyl groups include groups having from 3 to 13 ring atoms(i.e., C₃₋₁₃ cycloalkyl). Whenever it appears herein, a numerical rangesuch as “3 to 10” refers to each integer in the given range; e.g., “3 to13 carbon atoms” means that the cycloalkyl group can consist of 3 carbonatoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 13carbon atoms. The term “cycloalkyl” also includes bridged andspiro-fused cyclic structures containing no heteroatoms. The term alsoincludes monocyclic or fused-ring polycyclic (i.e., rings which shareadjacent pairs of ring atoms) groups. Polycyclic aryl groups includebicycles, bicycles, tetracycles, and the like. In some embodiments,“cycloalkyl” can be a C₃₋₈ cycloalkyl radical. In some embodiments,“cycloalkyl” can be a C₃₋₅ cycloalkyl radical. Illustrative examples ofcycloalkyl groups include, but are not limited to the followingmoieties: C₃₋₆ carbocyclyl groups include, without limitation,cyclopropyl (C₃), cyclobutyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆) and the like.Examples of C₃₋₇ carbocyclyl groups include norbornyl (C₇). Examples ofC₃₋₈ carbocyclyl groups include the aforementioned C₃₋₇ carbocyclylgroups as well as cycloheptyl(C₇), cycloheptadienyl (C₇),cycloheptatrienyl (C₇), cyclooctyl (C₈), bicyclo[2.2.1]heptanyl,bicyclo[2.2.2]octanyl, and the like. Examples of C₃₋₁₃ carbocyclylgroups include the aforementioned C₃₋₈ carbocyclyl groups as well asoctahydro-1H indenyl, decahydronaphthalenyl, spiro[4.5]decanyl and thelike. Unless stated otherwise in the specification, a cycloalkyl groupcan be optionally substituted by one or more substituents whichindependently include: acyl, Alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)N(R^(a))₂ (where t is 1 or 2), —P(═O)(R^(a))(R^(a)), or—O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen, alkyl,haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein. The terms “cycloalkenyl” and “cycloalkynyl” mirror the abovedescription of “cycloalkyl” wherein the prefix “alk” is replaced with“alken” or “alkyn” respectively, and the parent “alkenyl” or “alkynyl”terms are as described herein. For example, a cycloalkenyl group canhave 3 to 13 ring atoms, such as 5 to 8 ring atoms. In some embodiments,a cycloalkynyl group can have 5 to 13 ring atoms.

“Cycloalkyl-alkyl” refers to a -(cycloalkyl)alkyl radical wherecycloalkyl and alkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for cycloalkyl and alkyl respectively. The“cycloalkyl-alkyl” is bonded to the parent molecular structure throughthe cycloalkyl group. The terms “cycloalkyl-alkenyl” and“cycloalkyl-alkynyl” mirror the above description of “cycloalkyl-alkyl”wherein the term “alkyl” is replaced with “alkenyl” or “alkynyl”respectively, and “alkenyl” or “alkynyl” are as described herein.

“Cycloalkyl-heterocycloalkyl” refers to a -(cycloalkyl) heterocycylalkylradical where cycloalkyl and heterocycloalkyl are as disclosed hereinand which are optionally substituted by one or more of the substituentsdescribed as suitable substituents for heterocycloalkyl and cycloalkylrespectively. The “cycloalkyl-heterocycloalkyl” is bonded to the parentmolecular structure through the cycloalkyl group.

“Cycloalkyl-heteroaryl” refers to a -(cycloalkyl) heteroaryl radicalwhere cycloalkyl and heteroaryl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroaryl and cycloalkyl respectively. The“cycloalkylheteroaryl” is bonded to the parent molecular structurethrough the cycloalkyl group.

As used herein, a “covalent bond” or “direct bond” refers to a singlebond joining two groups.

“Ester” refers to a radical of formula —C(O)OR^(b) or —R_(b)OC(O)—,where R^(b) is selected from alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl. Any amine, hydroxy, or carboxyl side chainon the compounds described herein can be esterified. The procedures andspecific groups to make such esters are known to those of skill in theart and can readily be found in reference sources such as Greene andWuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley &Sons, New York, N.Y., 1999, which is incorporated herein by reference inits entirety. Unless stated otherwise in the specification, an estergroup can be optionally substituted by one or more substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)N(R^(a))₂ (where t is 1 or 2), —P(═O)(Ra^(b))(R^(a)),or —O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen, alkyl,haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Ether” refers to a —O—R^(b)—O— radical where each R^(b) isindependently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Halo”, “halide”, or, alternatively, “halogen” means fluoro, chloro,bromo or iodo. The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and“haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures thatare substituted with one or more halo groups or with combinationsthereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” includehaloalkyl and haloalkoxy groups, respectively, in which the halo isfluorine, such as, but not limited to, trifluoromethyl, difluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Eachof the alkyl, alkenyl, alkynyl and alkoxy groups are as defined hereinand can be optionally further substituted as defined herein.

“Heteroalkyl”, “heteroalkenyl” and “heteroalkynyl” include alkyl,alkenyl and alkynyl radicals, respectively, which have one or moreskeletal chain atoms selected from an atom other than carbon, e.g.,oxygen, nitrogen, sulfur, phosphorus or combinations thereof. Anumerical range can be given, e.g., C₁₋₄ heteroalkyl which refers to thechain length in total, which in this example is 4 atoms long. Forexample, a —CH₂OCH₂CH₃ radical is referred to as a “C₄” heteroalkyl,which includes the heteroatom center in the atom chain lengthdescription. Connection to the parent molecular structure can be througheither a heteroatom or a carbon in the heteroalkyl chain. For example,an N-containing heteroalkyl moiety refers to a group in which at leastone of the skeletal atoms is a nitrogen atom. One or more heteroatom(s)in the heteroalkyl radical can be optionally oxidized. One or morenitrogen atoms, if present, can also be optionally quaternized. Forexample, heteroalkyl also includes skeletal chains substituted with oneor more nitrogen oxide (—O—) substituents. Exemplary heteroalkyl groupsinclude, without limitation, ethers such as methoxyethanyl(—CH₂CH₂OCH₃), ethoxymethanyl (—CH₂OCH₂CH₃), (methoxymethoxy)ethanyl(—CH₂CH₂OCH₂OCH₃), (methoxymethoxy) methanyl (—CH₂OCH₂OCH₃) and(methoxyethoxy)methanyl (—CH₂OCH₂CH₂OCH₃) and the like; amines such as(—CH₂CH₂NHCH₃, —CH₂CH₂N(CH₃)₂, —CH₂NHCH₂CH₃, —CH₂N(CH₂CH₃)(CH₃)) and thelike. Heteroalkyl, heteroalkenyl, and heteroalkynyl groups can each beoptionally substituted by one or more substituents which independentlyinclude: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl,aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide, carbonate,carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl,heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester,ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo,phosphate, phosphonate, phosphinate, silyl, sulfinyl, sulfonyl,sulfonamidyl, sulfoxyl, sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a),—N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)N(R^(a))₂ (where t is 1 or 2), —P(═O)(R^(a))(R^(a)), or—O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen, alkyl,haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Heteroalkyl-aryl” refers to a -(heteroalkyl)aryl radical whereheteroalkyl and aryl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroalkyl and aryl respectively. The“heteroalkyl-aryl” is bonded to the parent molecular structure throughan atom of the heteroalkyl group.

“Heteroalkyl-heteroaryl” refers to a -(heteroalkyl)heteroaryl radicalwhere heteroalkyl and heteroaryl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroalkyl and heteroaryl respectively. The“heteroalkylheteroaryl” is bonded to the parent molecular structurethrough an atom of the heteroalkyl group.

“Heteroalkyl-heterocycloalkyl” refers to a-(heteroalkyl)heterocycloalkyl radical where heteroalkyl andheterocycloalkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroalkyl and heterocycloalkyl respectively. The“heteroalkyl-heterocycloalkyl” is bonded to the parent molecularstructure through an atom of the heteroalkyl group.

“Heteroalkyl-cycloalkyl” refers to a -(heteroalkyl) cycloalkyl radicalwhere heteroalkyl and cycloalkyl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroalkyl and cycloalkyl respectively. The“heteroalkylcycloalkyl” is bonded to the parent molecular structurethrough an atom of the heteroalkyl group.

“Heteroaryl” or, alternatively, “heteroaromatic” refers to a refers to aradical of a 5-18 membered monocyclic or polycyclic (e.g., bicyclic,tricyclic, tetracyclic and the like) aromatic ring system (e.g., having6, 10 or 14 π electrons shared in a cyclic array) having ring carbonatoms and 1-6 ring heteroatoms provided in the aromatic ring system,wherein each heteroatom is independently selected from nitrogen, oxygen,phosphorous and sulfur (“5-18 membered heteroaryl”). Heteroarylpolycyclic ring systems can include one or more heteroatoms in one orboth rings. Whenever it appears herein, a numerical range such as “5 to18” refers to each integer in the given range; e.g., “5 to 18 ringatoms” means that the heteroaryl group can consist of 5 ring atoms, 6ring atoms, etc., up to and including 18 ring atoms. In some instances,a heteroaryl can have 5 to 14 ring atoms. In some embodiments, theheteroaryl has, for example, bivalent radicals derived from univalentheteroaryl radicals whose names end in “-yl” by removal of one hydrogenatom from the atom with the free valence are named by adding “-ene” tothe name of the corresponding univalent radical, e.g., a pyridyl groupwith two points of attachment is a pyridylene.

For example, an N-containing “heteroaromatic” or “heteroaryl” moietyrefers to an aromatic group in which at least one of the skeletal atomsof the ring is a nitrogen atom. One or more heteroatom(s) in theheteroaryl radical can be optionally oxidized. One or more nitrogenatoms, if present, can also be optionally quaternized. Heteroaryl alsoincludes ring systems substituted with one or more nitrogen oxide (—O—)substituents, such as pyridinyl N-oxides. The heteroaryl is attached tothe parent molecular structure through any atom of the ring(s).

“Heteroaryl” also includes ring systems wherein the heteroaryl ring, asdefined above, is fused with one or more aryl groups wherein the pointof attachment to the parent molecular structure is either on the aryl oron the heteroaryl ring, or wherein the heteroaryl ring, as definedabove, is fused with one or more cycloalkyl or heterocycyl groupswherein the point of attachment to the parent molecular structure is onthe heteroaryl ring. For polycyclic heteroaryl groups wherein one ringdoes not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl andthe like), the point of attachment to the parent molecular structure canbe on either ring, i.e., either the ring bearing a heteroatom (e.g.,2-indolyl) or the ring that does not contain a heteroatom (e.g.,5-indolyl). In some embodiments, a heteroaryl group is a 5-10 memberedaromatic ring system having ring carbon atoms and 1-4 ring heteroatomsprovided in the aromatic ring system, wherein each heteroatom isindependently selected from nitrogen, oxygen, phosphorous, and sulfur(“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group isa 5-8 membered aromatic ring system having ring carbon atoms and 1-4ring heteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen, phosphorous,and sulfur (“5-8 membered heteroaryl”). In some embodiments, aheteroaryl group is a 5-6 membered aromatic ring system having ringcarbon atoms and 1-4 ring heteroatoms provided in the aromatic ringsystem, wherein each heteroatom is independently selected from nitrogen,oxygen, phosphorous, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, phosphorous, and sulfur. In someembodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatomsselected from nitrogen, oxygen, phosphorous, and sulfur. In someembodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selectedfrom nitrogen, oxygen, phosphorous, and sulfur.

Examples of heteroaryls include, but are not limited to, azepinyl,acridnyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl,benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]doxepinyl, benzo[b][1,4] oxazinyl, 1,4-benzodoxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl,benzopyranonyl, benzofurazanyl, benzothiazolyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo [3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d] pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo [4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl,thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl,thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e., thienyl). Unless stated otherwisein the specification, a heteroaryl moiety can be optionally substitutedby one or more substituents which independently include: acyl, alkyl,alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy,amino, amido, amidino, imino, azide, carbonate, carbamate, carbonyl,heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxy,cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto, thio,alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate,phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl,sulfonate, urea, —Si(R^(a))₃, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)N(R^(a))₂ (where t is 1 or2), —P(═O)(R^(a))(R^(a)), or —O—P(═O)(OR^(a))₂ where each R^(a) isindependently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl,aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl, and each of these moieties can be optionallysubstituted as defined herein.

“Heteroaryl-alkyl” refers to a -(heteroaryl)alkyl radical whereheteroaryl and alkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heteroaryl and alkyl respectively. The “heteroarylalkyl” is bonded to the parent molecular structure through any atom ofthe heteroaryl group.

“Heteroaryl-heterocycloalkyl” refers to an -(heteroaryl)heterocycloalkylradical where heteroaryl and heterocycloalkyl are as disclosed hereinand which are optionally substituted by one or more of the substituentsdescribed as suitable substituents for heteroaryl and heterocycloalkylrespectively. The “heteroaryl-heterocycloalkyl” is bonded to the parentmolecular structure through an atom of the heteroaryl group.

“Heteroaryl-cycloalkyl” refers to an -(heteroaryl)cycloalkyl radicalwhere heteroaryl and cycloalkyl are as disclosed herein and which areoptionally substituted by one or more of the substituents described assuitable substituents for heteroaryl and cycloalkyl respectively. The“heteroarylcycloalkyl” is bonded to the parent molecular structurethrough a carbon atom of the heteroaryl group.

“Heterocyclyl”, “heterocycloalkyl” or “heterocarbocyclyl” each refer toany 3 to 18-membered non-aromatic radical monocyclic or polycyclicmoiety comprising at least one heteroatom selected from nitrogen,oxygen, phosphorous and sulfur. A heterocyclyl group can be amonocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein thepolycyclic ring systems can be a fused, bridged or spiro ring system.Heterocyclyl polycyclic ring systems can include one or more heteroatomsin one or both rings. A heterocycyl group can be saturated or partiallyunsaturated. Partially unsaturated heterocycloalkyl groups can be termed“heterocycloalkenyl” if the heterocyclyl contains at least one doublebond, or “heterocycloalkynyl” if the heterocyclyl contains at least onetriple bond. Whenever it appears herein, a numerical range such as “5 to18” refers to each integer in the given range; e.g., “5 to 18 ringatoms” means that the heterocyclyl group can consist of 5 ring atoms, 6ring atoms, etc., up to and including 18 ring atoms. For example,bivalent radicals derived from univalent heterocyclyl radicals whosenames end in “-yl” by removal of one hydrogen atom from the atom withthe free valence are named by adding “-ene” to the name of thecorresponding univalent radical, e.g., a piperidine group with twopoints of attachment is a piperidylene.

An N-containing heterocyclyl moiety refers to an non-aromatic group inwhich at least one of the ring atoms is a nitrogen atom. Theheteroatom(s) in the heterocyclyl radical can be optionally oxidized.One or more nitrogen atoms, if present, can be optionally quaternized.Heterocyclyl also includes ring systems substituted with one or morenitrogen oxide (—O—) substituents, such as piperidinyl N-oxides. Theheterocyclyl is attached to the parent molecular structure through anyatom of any of the ring(s).

“Heterocyclyl” also includes ring systems wherein the heterocycyl ring,as defined above, is fused with one or more carbocycyl groups whereinthe point of attachment is either on the carbocycyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment to the parent molecular structure is on the heterocyclylring. In some embodiments, a heterocyclyl group is a 5-14 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, phosphorous and sulfur (“5-14 membered heterocyclyl”).In some embodiments, a heterocycyl group is a 3-10 membered non-aromaticring system having ring carbon atoms and 1-4 ring heteroatoms, whereineach heteroatom is independently selected from nitrogen, oxygen,phosphorous and sulfur (“3-10 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-8 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, phosphorousand sulfur (“5-8 membered heterocyclyl”). In some embodiments, aheterocyclyl group is a 5-6 membered non-aromatic ring system havingring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom isindependently selected from nitrogen, oxygen, phosphorous and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygenphosphorous and sulfur. In some embodiments, the 5-6 memberedheterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen,phosphorous and sulfur. In some embodiments, the 5-6 memberedheterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen,phosphorous and sulfur.

Exemplary 3-membered heterocyclyls containing 1 heteroatom include,without limitation, azirdinyl, oxiranyl, and thiorenyl. Exemplary4-membered heterocyclyls containing 1 heteroatom include, withoutlimitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-memberedheterocyclyls containing 1 heteroatom include, without limitation,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione.Exemplary 5-membered heterocyclyls containing 2 heteroatoms include,without limitation, dioxolanyl, oxathiolanyl, thiazolidinyl, anddithiolanyl. Exemplary 5-membered heterocyclyls containing 3 heteroatomsinclude, without limitation, triazolinyl, diazolonyl, oxadiazolinyl, andthiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1heteroatom include, without limitation, piperidinyl, tetrahydropyranyl,dihydropyridinyl, and thianyl. Exemplary 6 membered heterocyclyl groupscontaining 2 heteroatoms include, without limitation, piperazinyl,morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, and triazinanyl.Exemplary 7-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing 1 heteroatom include, withoutlimitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclicheterocyclyl groups include, without limitation, indolinyl,isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,tetrahydrobenzothienyl, tetrahydrobenzofuranyl, benzoxanyl,benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl,benzothianyl, tetrahydroindolyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl,3-1H-benzimidazol-2-one, (1-substituted)-2-oxo-benzimidazol-3-yl,octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl,decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole,phenanthridinyl, indolinyl, phthalimidyl, naphthalimidyl, chromanyl,chromenyl, 1H-benzo[e] [1,4]diazepinyl,1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo [3,2-b]pyranyl,5,7-dihydro-4H-thieno [2,3-c]pyranyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, hydrofuro[2,3-b]pyridinyl,4,5,6,7 tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

Unless stated otherwise in the specification, a heterocyclyl moiety canbe optionally substituted by one or more substituents whichindependently include: acyl, alkyl, alkenyl, alkynyl, alkoxy, alkylaryl,cycloalkyl, aralkyl, aryl, aryloxy, amino, amido, amidino, imino, azide,carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl,heteroarylalkyl, heterocycloalkyl, hydroxy, cyano, halo, haloalkoxy,haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio,thiocarbonyl, nitro, oxo, phosphate, phosphonate, phosphinate, silyl,sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea,—Si(R^(a))₃, —OR⁸, —SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(a),—N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂, —N(R^(a))C(NR^(a))N(R^(a))₂,—N(R^(a))S(O)_(t)N(R^(a))₂ (where t is 1 or 2), —P(═O)(R^(a))(R^(a)), or—O—P(═O)(OR^(a))₂ where each R^(a) is independently hydrogen, alkyl,haloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each of these moieties can be optionally substituted as definedherein.

“Heterocyclyl-alkyl” refers to a -(heterocyclyl)alkyl radical whereheterocyclyl and alkyl are as disclosed herein and which are optionallysubstituted by one or more of the substituents described as suitablesubstituents for heterocyclyl and alkyl respectively. The“heterocyclyl-alkyl” is bonded to the parent molecular structure throughany atom of the heterocyclyl group. The terms “heterocyclyl-alkenyl” and“heterocyclyl-alkynyl” mirror the above description of“heterocyclyl-alkyl” wherein the term “alkyl” is replaced with “alkenyl”or “alkynyl” respectively, and “alkenyl” or “alkynyl” are as describedherein.

“Imino” refers to the “—(C═N)—R^(b) radical where R^(b) is selected fromhydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein.

“Moiety” refers to a specific segment or functional group of a molecule.Chemical moieties are often recognized chemical entities embedded in orappended to a molecule.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Phosphate” refers to a —O—P(═O)(OR^(b))₂ radical, where each R^(b) isindependently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, when R^(b) is hydrogen anddepending on the pH, the hydrogen can be replaced by an appropriatelycharged counter ion.

“Phosphonate” refers to a —O—(P═O)(R^(b))(OR^(b)) radical, where eachR^(b) is independently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, when R^(b) is hydrogen anddepending on the pH, the hydrogen can be replaced by an appropriatelycharged counter ion.

“Phosphinate” refers to a —P(═O)(R^(b))(OR^(b)) radical, where eachR^(b) is independently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, when R^(b) is hydrogen anddepending on the pH, the hydrogen can be replaced by an appropriatelycharged counter ion.

“Phosphine oxide” refers to a —P(═O)(R^(b))(R^(b)) radical, where eachR^(b) is independently selected from hydrogen, alkyl, alkenyl, alkynyl,haloalkyl, heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. In some embodiments, when R^(b) is hydrogen anddepending on the pH, the hydrogen can be replaced by an appropriatelycharged counter ion.

“Silyl” refers to a —Si(R^(b))₃ radical where each R^(b) isindependently selected from alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Sulfanyl”, “sulfide”, and “thio” each refer to the radical —S—R^(b),wherein R^(b) is selected from alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein. For instance, an “alkylthio” refers to the“alkyl-S—” radical, and “arylthio” refers to the “aryl-S—” radical, eachof which are bound to the parent molecular group through the S atom. Theterms “sulfide”, “thiol”, “mercapto”, and “mercaptan” can also eachrefer to the group —R^(b)SH.

“Sulfinyl” or “sulfoxide” refer to the —S(O)—R^(b) radical, wherein for“sulfinyl”, R^(b) is H and for “sulfoxide”, R^(b) is selected fromalkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bonded through a chaincarbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl(bonded through a ring carbon), heterocycloalkylalkyl, heteroaryl(bonded through a ring carbon) or heteroarylalkyl, unless statedotherwise in the specification, each of which moiety can itself beoptionally substituted as described herein.

“Sulfonyl” or “sulfone” refer to the —S(O₂)—R^(b) radical, wherein R^(b)is selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl,heteroalkyl (bonded through a chain carbon), cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bonded through a ringcarbon), heterocycloalkylalkyl, heteroaryl (bonded through a ringcarbon) or heteroarylalkyl, unless stated otherwise in thespecification, each of which moiety can itself be optionally substitutedas described herein.

“Sulfonamidyl” or “sulfonamido” refer to the following radicals:—S(═O)₂—(R^(b))₂, —N(R^(b))—S(═O)₂—R^(b), —S(═O)₂—N(R^(b))—, or—N(R^(b))—S(═O)₂—, where each R_(b) is independently selected fromhydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein. The R^(b) groups in—S(═O)₂—(R^(b))₂ can be taken together with the nitrogen to which theyare attached to form a 4-, 5-, 6-, or 7-membered heterocyclyl ring. Insome embodiments, the term designates a C₁₋₄ sulfonamido, wherein eachR^(b) in the sulfonamido contains 1 carbon, 2 carbons, 3 carbons, or 4carbons total.

“Sulfoxyl” or “sulfoxide” refer to a —S(═O)₂OH radical.

“Sulfonate” refers to a —S(═O)₂—OR^(b) radical, wherein R^(b) isselected from alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl (bondedthrough a chain carbon), cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl (bonded through a ring carbon), heterocycloalkylalkyl,heteroaryl (bonded through a ring carbon) or heteroarylalkyl, unlessstated otherwise in the specification, each of which moiety can itselfbe optionally substituted as described herein.

“Thiocarbonyl” refers to a —(C═S)— radical.

“Urea” refers to a —N(R^(b))—(C═O)—N(R^(b))₂ or —N(R^(b))—(C═O—N(R^(b))—radical, where each R^(b) is independently selected from alkyl, alkenyl,alkynyl, haloalkyl, heteroalkyl (bonded through a chain carbon),cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl (bondedthrough a ring carbon), heterocycloalkylalkyl, heteroaryl (bondedthrough a ring carbon) or heteroarylalkyl, unless stated otherwise inthe specification, each of which moiety can itself be optionallysubstituted as described herein.

Where substituent groups are specified by their conventional chemicalFormulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

A “leaving group or atom” is any group or atom that will, under thereaction conditions, cleave from the starting material, thus promotingreaction at a specified site. Suitable non-limiting examples of suchgroups unless otherwise specified include halogen atoms, mesyloxy,p-nitrobenzensulphonyloxy, trifluoromethyloxy, and tosyloxy groups.

“Protecting group” has the meaning conventionally associated with it inorganic synthesis, i.e., a group that selectively blocks one or morereactive sites in a multifunctional compound such that a chemicalreaction can be carried out selectively on another unprotected reactivesite and such that the group can readily be removed after the selectivereaction is complete. Non-limiting embodiments of functional groups thatcan be masked with a protecting group include an amine, hydroxy, thiol,carboxylic acid, and aldehyde. For example, a hydroxy protected form iswhere at least one of the hydroxy groups present in a compound isprotected with a hydroxy protecting group. A variety of protectinggroups are disclosed, for example, in T. H. Greene and R G. M. Wuts,Protective Groups in Organic Synthesis, Third Edition, John Wiley &Sons, New York (1999), incorporated herein by reference in its entirety.For additional background information on protecting group methodologies(materials, methods and strategies for protection and deprotection) andother synthetic chemistry transformations useful in producing thecompounds described herein, see in R. Larock, Comprehensive organicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3rd. Ed., John Wiley and Sons(1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995). These references are incorporated herein by reference in theirentirety.

The terms “substituted” or “substitution” mean that at least onehydrogen present on a group atom (e.g., a carbon or nitrogen atom) isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution for the hydrogen results in a stable compound, e.g., acompound which does not spontaneously undergo transformation such as byrearrangement, cyclization, elimination, or other reaction. Unlessotherwise indicated, a “substituted” group can have a substituent at oneor more substitutable positions of the group, and when more than oneposition in any given structure is substituted, the substituent iseither the same or different at each position. Substituents include oneor more group(s) individually and independently selected from acyl,alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl,aryloxy, amino, amido, amidino, imino, azide, carbonate, carbamate,carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl,hydroxy, cyano, halo, haloalkoxy, haloalkyl, ester, ether, mercapto,thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate,phosphonate, phosphinate, silyl, sulfinyl, sulfonyl, sulfonamidyl,sulfoxyl, sulfonate, urea, —Si(R^(a))₃, —OR², —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R_(a), —C(O)OR^(a), —OC(O)N(R^(a))₂, —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(a), —N(R^(a))C(O)R^(a), —N(R^(a))C(O)N(R^(a))₂,—N(R^(a))C(NR^(a))N(R^(a))₂, —N(R^(a))S(O)_(t)N(R^(a))₂ (where t is 1 or2), —P(═O)(R^(a))R^(a)), or —O—P(═O)(OR^(a))₂ where each R^(a) isindependently hydrogen, alkyl, haloalkyl, carbocyclyl, carbocyclylalkyl,aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl, and each of these moieties can be optionallysubstituted as defined herein. For example, a cycloalkyl substituent canhave a halide substituted at one or more ring carbons, and the like. Theprotecting groups that can form the protective derivatives of the abovesubstituents are known to those of skill in the art and can be found inreferences such as Greene and Wuts, above.

Suitable substituents include, but are not limited to, haloalkyl andtrihaloalkyl, alkoxyalkyl, halophenyl, -M-heteroaryl, -M-heterocycle,-M-aryl, -M-OR^(a), -M-SR^(a), -M-N(R^(a))₂,-M-OC(O)N(R^(a))₂-M-C(═NR^(a))N(R^(a))₂, -M-C(═NR^(a))OR^(a),-M-P(O)R^(a))₂, Si(R^(a))₃, -M-NR^(a)C(O)R^(a), -M-NR^(a)C(O)OR^(a),-M-C(O)R^(a), -M-C(═S)R^(a), -M-C(═S)NR^(a)R^(a), -M-C(O)N(R^(a))₂,-M-C(O)NR^(a)-M-N(R^(a))₂, -M-NR^(a)C(NR^(a))N(R^(a))₂,-M-NR^(a)C(S)N(R^(a))_(2,) -M-S(O)₂R^(a), -M C(O)R^(a), -M-OC(O)R^(a),-MC(O)SR^(a), -M-S(O)₂N(R)₂, —C(O)-M-C(O)R^(a), -MCO₂R^(a),-MC(═O)N(R^(a))₂, -M-C(═NH)N(R^(a))₂, and -M-OC(═NH)N(R^(a))₂ (wherein Mis a C₁₋₆ alkyl group).

When a ring system (e.g., cycloalkyl, heterocyclyl, aryl, or heteroaryl)is substituted with a number of substituents varying within an expresslydefined range, it is understood that the total number of substituentsdoes not exceed the normal available valencies under the existingconditions. Thus, for example, a phenyl ring substituted with “p”substituents (where “p” ranges from 0 to 5) can have 0 to 5substituents, whereas it is understood that a pyridinyl ring substitutedwith “p” substituents has a number of substituents ranging from 0 to 4.The maximum number of substituents that a group in the disclosedcompounds can have can be easily determined. The substituted groupencompasses only those combinations of substituents and variables thatresult in a stable or chemically feasible compound. A stable compound orchemically feasible compound is one that, among other factors, hasstability sufficient to permit its preparation and detection. In someembodiments, disclosed compounds are sufficiently stable that they arenot substantially altered when kept at a temperature of 40° C. or less,in the absence of moisture (e.g., less than about 10%, less than about5%, less than about 2%, less than about 1%, or less than about 0.5%) orother chemically reactive conditions, for e.g., at least about 3 days,at least about a week, at least about 2 weeks, at least about 4 weeks,or at least about 6 weeks.

The terms “combine, combining, to combine, combination” refer to theaction of adding at least one chemical substance to another chemicalsubstance(s) either sequentially or simultaneously. In some embodiments,bringing these chemical substances together can result in transformationof the initial chemical substances into one or more different chemicalsubstances. This transformation can occur through one or more chemicalreactions, e.g., where covalent bonds are formed, broken, rearranged andthe like. A non-limiting example can include hydrolysis of an ester intoan alcohol and carboxylic acid which can result from the combination ofthe ester with a suitable base. In another non-limiting example, an arylfluoride can be combined with an amine to provide an aryl amine througha substitution process. These terms also include changes in associationof charged chemical substances and creation of charged chemicalsubstances, such as, but not limited to, N-oxide formation, acidaddition salt formation, basic addition salt formation, and the like.These terms include the creation and/or transformation of radicalchemical substances and isotopically labeled chemical substances.

The terms “convert, converting, to convert, conversion” refer to asubset of “combination” and its grammatical equivalents, where theaction of one or more reagents transforms one or more functional groupson a chemical substance to other functional group(s). For example, aconversion includes, but is not limited to, transforming a nitrofunctional group on a chemical substance to an amine with a reducingagent. Conversions also include changes in charged chemical substances,radical chemical substances and isotopically labeled chemicalsubstances. However, the term “convert” does not include alteration ofconserved bonds in disclosed geniuses and compounds.

Compounds

In one aspect, provided herein are compounds of Formula I:

wherein:

A is selected from

-   -   X₁ is selected from N and CR₁;

X₂ is selected from N and CR₂;

X₃ is selected from N and CR₄;

each X₄ is independently selected from N and CR₇;

-   -   X₅ is selected from N and CR₈;

X₆ is selected from N and CR₉;

R₁ is selected from H, acyl, alkyl, alkenyl, alkynyl, alkoxy, aryloxy,alkoxycarbonyl, amido, amino, carbonate, carbamate, carbonyl, carboxyl,ester, halo, CN, NO₂, hydroxy, phosphate, phosphonate, phosphinate,phosphine oxide, mercapto, thio, alkylthio, arylthio, thiocarbonyl,sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, cycloalkyl,heterocyclyl, aryl, and heteroaryl, each of which is substituted with 0,1, 2, or 3 R₁₂;

-   -   R₂, R₃, and R₄ are each independently selected from H, alkyl,        alkoxy, halo, CN, and NO₂, each of which is substituted with 0,        1, 2, or 3 R₁₂;    -   R₅ is selected from H, alkyl, alkenyl, alkynyl, —NR₁₀R₁₁, —OR₁₁,        and —SR₁₁, each of which is independently substituted with 0, 1,        2, or 3 R₁₂; or when R₅ is —NR₁₀R₁₁, then R₁₀ and R₁₁ can be        taken together with the nitrogen atom to which they are attached        to form a heterocyclyl or heteroaryl group, each of which is        substituted with 0, 1, 2, or 3 R₁₂;    -   R₄ and R₅ can be taken together with the carbon atoms to which        they are attached to form a cycloalkyl, heterocyclyl, aryl, or        heteroaryl group, each of which is substituted with 0, 1, 2, or        3 R₁₂;    -   R₆ is selected from H, acyl, alkyl, amino, halo, CN, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl, each of which is        substituted with 0, 1, 2, or 3 R₁₂;    -   each R₇ is independently selected from H, alkyl, alkenyl,        alkynyl, alkoxy, amido, amino, carbonyl, ester, halo, CN, and        NO₂, each of which is substituted with 0, 1, 2, or 3 R₁₂; and        wherein any two adjacent R₇ groups can be taken together with        the carbon atoms to which they are attached to form a        cycloalkyl, heterocyclyl, aryl, or heteroaryl ring, each of        which is substituted with 0, 1, 2, or 3 R₁₂;    -   R₈ is selected from H, acyl, alkyl, amido, amino, carbamate,        carbonyl, and urea, each of which is substituted with 0, 1, 2,        or 3 R₁₂;    -   R₉ is selected from H, alkyl, alkenyl, alkynyl, alkoxy, amino,        amido, ester, halo, CN, NO₂, cycloalkyl, heterocyclyl, aryl, and        heteroaryl, each of which is substituted with 0, 1, 2, or 3 R₁₂;    -   each R₁₀ and R₁₁ are independently selected from H, acyl, alkyl,        carbonyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,        each of which is independently substituted with 0, 1, 2, or 3        R₁₂; and    -   each R₁₂ is independently selected from acyl, alkyl, alkenyl,        alkynyl, alkoxy, aryloxy, alkoxycarbonyl, amido, amino,        carbonate, carbamate, carbonyl, ester, halo, CN, NO₂, hydroxyl,        phosphate, phosphonate, phosphinate, phosphine oxide, thio,        alkylthio, arylthio, thiocarbonyl, sulfonyl, sulfonamidyl,        sulfoxyl, sulfonate, urea, cycloalkyl, heterocycloalkyl, aryl,        and heteroaryl.

In some embodiments, the compound of Formula I can be a compound ofFormula Aa:

In some embodiments, the compound of Formula I can be a compound ofFormula Ab:

In some embodiments, the compound of Formula I can be a compound ofFormula Ac:

In some embodiments, the compound of Formula I can be a compound ofFormula Ad:

In some embodiments, the compound of Formula I can be a compound ofFormula Ae:

In some embodiments, the compound of Formula I can be a compound ofFormula Af:

In some embodiments, the compound of Formula I can be a compound ofFormula Ba:

In some embodiments, the compound of Formula I can be a compound ofFormula Bb:

In some embodiments, the compound of Formula I can be a compound ofFormula Bc:

In some embodiments, the compound of Formula I can be a compound ofFormula Bd:

In some embodiments, the compound of Formula I can be a compound ofFormula Be:

In some embodiments, the compound of Formula I can be a compound ofFormula Bf:

In some embodiments, the compound of Formula I can be a compound ofFormula Bg:

In some embodiments, the compound of Formula I can be a compound ofFormula Bh:

In some embodiments, the compound of Formula I can be a compound ofFormula Bi:

The following embodiments apply to any and all compounds of Formula I,including, but not limited to, Formulae Aa, Ab, Ac, Ad, Ae, Af, Ba, Bb,Bc, Bd, Be, Bf, Bg, Bh and Bi.

In some embodiments, X₁ can be N. In other embodiments, X₁ can be CR₁.In some embodiments, X₂ can be N. In other embodiments, X₂ can be CR₂,where R₂ is H. In some embodiments, X₁ can be N, and X₂ can be N. Insome embodiments, X₁ can be CR₁, and X₂ can be N. In other embodiments,X₁ can be N, and X₂ can be CR₂, where R₂ is H. In further embodiments,X₁ can be CR₁, and X₂ can be CR₂, where R₂ is H. In some embodiments, X₃can be N. In other embodiments, X₃ can be CR₄, where R₄ is H. In someembodiments, X₁ can be CR₁, X₂ can be N, and X₃ can be N. In someembodiments, X₁ can be CR₁, X₂ can be N, and X₃ can be CR₄, where R₄ isH. In further embodiments, X₁ can be N, X₂ can be N, and X₃ can be N. Insome embodiments, X₁ can be N, X₂ can be N, and X₃ can be CR₄, where R₄is H.

In some embodiments, A can be

In some embodiments, A can be

In some embodiments, A can be

and X₄ can be N. In some embodiments, A can be

and X₄ can be CR₇, where R₇ is selected from H alkyl, alkoxy, amido, andCN. In further embodiments, A can be

and X₄ can be CR₇, where R₇ is alkoxy, and the alkoxy is —OMe. In someembodiments, A can be

and X₅ can be N. In other embodiments, A can be

and X₅ can be CR₈, where R₈ is selected from H and alkyl. In furtherembodiments, A can be

X₅ can be CR₈, where R₈ is alkyl, and the alkyl is Me. In someembodiments, A can be

and X₆ can be N. In other embodiments, A can be

and X₆ can be CR₉, where R₉ is selected from H, heterocyclyl, aryl, andhetero each of which is substituted with 0, 1, or 2 R₁₂. In otherembodiments, A can be

X₆ can be CR₉, where R₉ is selected from

In some embodiments, A can be

In some embodiments, A can be

In some embodiments, A can be

In some embodiments, A can be

and X₄ can be N. In some embodiments, A can be

and X₄ can be CR₇, where R₇ is selected from H alkyl, alkoxy, amido, andCN. In further embodiments, A can be

and X₄ can be CR₇, where R₇ is alkoxy, and the alkoxy is —OMe. In someembodiments, A can be

and X₅ can be N. In other embodiments, A can be

and X₅ can be CR₈, where R₈ is selected from H and alkyl. In furtherembodiments, A can be

X₅ can be CR₈, where R₈ is alkyl, and the alkyl is Me. In someembodiments, A can be

and X₆ can be N. In other embodiments, A can be

and X₆ can be CR₉, where R₉ is selected from H, heterocyclyl, aryl, andheteroaryl, each of which is substituted with 0, 1, or 2 R₁₂. In otherembodiments, A can be

X₆ can be CR₉, where R₉ is selected from

In some embodiments, A can be

In other embodiments, A can be

In further embodiments, A can be

In some embodiments, A can be

In some embodiments, A can be

In some embodiments, A can be

and X₄ can be N. In some embodiments, A can be

and X₄ can be CR₇, where R₇ is selected from H alkyl, alkoxy, amido, andCN. In further embodiments, A can be

and X₄ can be CR₇, where R₇ is alkoxy, and the alkoxy is —OMe. In someembodiments, A can be

and X₅ can be N. In other embodiments, A can be

and X₅ can be CR₈, where R₈ is selected from H and alkyl. In furtherembodiments, A can be

X₅ can be CR₈, where R₈ is alkyl, and the alkyl is Me. In someembodiments, A can be

and X₆ can be N. In other embodiments, A can be

and X₆ can be CR₉, where R₉ is selected from H, heterocyclyl, aryl, andheteroaryl, each of which is substituted with 0, 1, or 2 R₁₂. In otherembodiments, A can be

X₆ can be CR₉, where R₉ is selected from

In some embodiments, A can be

In some embodiments, A can be

In some embodiments, A can be

and each X₄ can be CR₇, where R₇ is H. In other embodiments, A can be

X₄ can be CR₇, where any two adjacent R₇ groups can be taken togetherwith the carbon atoms to which they are attached to form a cycloalkyl,heterocyclyl, aryl, or heteroaryl ring, each of which can be substitutedwith 0, 1, 2, or 3 R₁₂. In other embodiments, A can be selected from

In some embodiments, A can be

In some embodiments, A can be

and X₄ can be N. In some embodiments, A can be

and X₄ can be CR₇, where R₇ is selected from H alkyl, alkoxy, amido,ester, cyclohexyl, and CN. In some embodiments, A can be

and X₄ can be CR₇, where R₇ is selected from H alkyl, alkoxy, amido, andCN. In further embodiments, A can be

and X₄ can be CR₇, where R₇ is alkoxy, and the alkoxy is —OMe. In otherembodiments, A can be

and R₈ can be selected from H and alkyl where the alkyl is substitutedwith 0 or 1 R₁₂, and R₁₂ is amino. In further embodiments, A can be

and R₈ can be alkyl, where the alkyl is Me or Et. In furtherembodiments, A can be

and R₈ can be alkyl, where the alkyl where the alk is substituted with 0or 1 R₁₂, where R₁₂ is amido or hydroxy. In some embodiments, A can be

and R₈ can be H. In some embodiments, A can be

and X₆ can be N. In other embodiments, A can be

and X₆ can be CR₉, where R₉ is selected from H, CN, alkyl, ester, amido,heterocyclyl, aryl, and heteroaryl, each of which is substituted with 0,1, or 2 R₁₂. In other embodiments, A can be

and X₆ can be CR₉, where R₉ is selected from H, heterocyclyl, aryl, andheteroaryl, each of which is substituted with 0, 1, or 2 R₁₂. In otherembodiments, A can be

X₆ can be CR₉,

where R₉ is selected from

In some embodiments, A can be

In some embodiments, A can be

and X₄ is CR₇, and R₇ is selected from cyano, ester, and heteroaryl. Inother embodiments, A can be

and X₄ is CR₇, and R₇ is ester. In further embodiments, A can be

and X₄ is CR₇, and R₇ is ester.

In some embodiments, A can be

In other embodiments, A can be

In further embodiments, A can be

In further embodiments, A can be

In other embodiments, A can be

In some embodiments, A can be

In some embodiments, A can be

In some embodiments, A can be

and X₄ can be N. In some embodiments, A can be

and X₄ can be CR₇, where R₇ is selected from H alkyl, alkoxy, amido, andCN. In further embodiments, A can be

and X₄ can be CR₇, where R₇ is alkoxy. In further embodiments, A can be

and X₄ can be CR₇, where R₇ is alkoxy, and the alkoxy is —OMe. In otherembodiments, A can be

and R₈ can be selected from H and alkyl. In further embodiments, A canbe

and R₈ can be alkyl, where the alkyl is Me. In some embodiments, A canbe

and R₈ can be H. In some embodiments, A can be

and X₆ can be N. In other embodiments, A can be

and X₆ can be CR₉, where R₉ is selected from H, heterocyclyl, aryl, andheteroaryl, each of which is substituted with 0, 1, or 2 R₁₂. In otherembodiments, A can be

X₆ can be CR₉, where R₉ is selected from

In some embodiments, A can be

selected from

In other embodiments, A can be

In further embodiments, A can be

In other embodiments, A can be

In some embodiments, A can be

In further embodiments, A can be

In some embodiments, R₁ can be selected from H, alkyl, alkenyl, alkynyl,amido, amino, ester, halo, CN, cycloalkyl, urea, phosphine oxide,heterocyclyl, aryl, and heteroaryl, each of which is substituted with 0,1, 2, or 3 R₁₂. In some embodiments, R₁ can be selected from H, alkyl,alkenyl, alkynyl, amido, amino, ester, halo, CN, cycloalkyl,heterocyclyl, aryl, and heteroaryl, each of which is substituted with 0,1, 2, or 3 R₁₂. In other embodiments, R₁ can be selected from H, alkyl,amido, ester, halo, and CN, each of which is substituted with 0, 1, or 2R₁₂. In further embodiments, R₁ can be ester or amido, each of which issubstituted with 1 or 2 R₁₂.

In some embodiments, R₁ can be ester substituted with one R₁₂. In someembodiments, the ester is selected from

In other embodiments, the ester can be selected from

In further embodiments, the ester can be selected from

In other embodiments, the ester can be selected from

In other embodiments, R₁ can be amide substituted with 1 or 2 R₁₂. Infurther embodiments, the amide can be selected from

In a further embodiment, the amide can be

In some embodiments, R₃ can be selected from H, alkyl, alkoxy, and halo.In other embodiments, R₃ can be alkoxy. In further embodiments, R₃ canbe alkoxy, where the alkoxy is —OMe.

In some embodiments, R₅ can be selected from H, alkynyl, —NR₁₀R₁₁, and—OR₁₁, each of which is independently substituted with 0, 1, 2, or 3R₁₂; or when R₅ is —NR₁₀R₁₁, then R₁₀ and R₁₁ can be taken together withthe nitrogen atom to which they are attached to form a heterocyclyl orheteroaryl group, each of which is substituted with 0, 1, 2, or 3 R₁₂.In other embodiments, R can be —NR₁₀R₁₁, where R₁₀ is alkyl, R₁₁ isalkyl substituted with 1 or 2 R₁₂, and R₁₂ is amino or heterocyclyl. Insome embodiments, R₅ can be —NR₁₀R₁₁, and R₁₀ and R₁₁ are taken togetherwith the nitrogen atom to which they are attached to form a heterocyclylor heteroaryl group, substituted with 0 or 1 R₁₂. In other embodiments,R₅ can be —OR₁₁, where R₁₁ is alkyl substituted with 0, 1 or 2 R₁₂, andeach R₁₂ is independently selected from heterocyclyl, heterocyclylalkyl,alkoxyalkyl, and aminoalkyl. In further embodiments, R can be alkynyl,where the alkynyl is substituted with one R₁₂, and R₁₂ alkylamino.

In some embodiments, R₅ can be selected from

In other embodiments, R₅ can be selected from

In some embodiments, R₅ can be selected from

In further embodiments, R₅ can be selected from

In some embodiments, Re can be H or alkyl substituted with 0 or 1 R₁₂.In some embodiments, R₆ can be H. In other embodiments, Re can be alkylsubstituted with one R₁₂, and R₁₂ is amino. In other embodiments, R₆ canbe alkyl substituted with one R₁₂, and R₁₂ is heterocyclyl. In someembodiments, Re can be selected from alkyl, CN, and halo.

In some embodiments, each R₇ can be independently selected from H,alkyl, alkenyl, alkynyl, alkoxy, amido, amino, carbonyl, ester, halo,CN, NO₂ and heteroaryl, each of which is substituted with 0, 1, 2, or 3R₁₂; and wherein any two adjacent R₇ groups can be taken together withthe carbon atoms to which they are attached to form a cycloalkyl,heterocyclyl, aryl, or heteroaryl ring, each of which is substitutedwith 0, 1, 2, or 3 R₁₂. In other embodiments, R^(a) can be selected fromH, acyl, alkyl, cycloalkyl, amido, amino, carbamate, carbonyl, and urea,each of which is substituted with 0, 1, 2, or 3 R₁₂.

In some embodiments, the compound of Formula I can have the followingaspects:

-   -   A is selected from

-   -   X₁ is selected from N and CR₁;    -   X₂ is N;

X₃ is CR₄;

-   -   X₄ is selected from N and CR₇;

X₆ is CR₉;

R₁ is selected from H, alkyl, and ester;

R₃ is alkoxy;

R₄ is H;

R₅ is —NR₁₀R₁₁;

R₆ is H;

R₇ is selected from H and alkoxy;

R₈ is selected from H and alkyl;

R₉ is selected from H, aryl, and heteroaryl, each of which issubstituted with 0 or 1 R₁₂, and R₁₂ is halo;

R₁₀ is alkyl; and

R₁₁ is alkyl substituted with one R₁₂, and R₁₂ is substituted with aminoor heterocyclyl.

In some embodiments, the compound of Formula I can have the followingaspects:

A is selected from

X₁ is CR₁;

X₂ is N;

X₃ is CR₄;

X₄ is CR₇;

X₆ is CR₉;

R₁ is selected from H, ester, halo, and CN;

R₃ is alkoxy;

R₄ is H;

-   -   R₅ is selected from H, alkynyl, —NR₁₀R₁₁, and —OR₁₁, each of        which is independently substituted with 0, 1, or 2 R₁₂, and R₁₂        is amino, alkoxy, or heterocyclyl; or when R₅ is —NR₁₀R₁₁, then        R₁₀ and R₁₁ can be taken together with the nitrogen atom to        which they are attached to form a heterocyclyl or heteroaryl        group, each of which is substituted with 1 R₁₂, and R₁₂ is alkyl        or amino;

R₆ is H;

R₇ is selected from H and alkoxy substituted with one R₁₂, and R₁₂ isamino or heterocyclyl;

R₈ is alkyl;

R₉ is selected from H and aryl substituted with 2 R₁₂, and R₁₂ is alkoxyor halo; and

R₁₀ and R₁₁ are each independently alkyl, each of which is independentlysubstituted with 0, 1, or 2 R₁₂, and R₁₂ is amino, alkoxy, orheterocyclyl.

In some aspects, the compound of Formula I can have the followingaspects:

A is selected from

-   -   X₁ is selected from N and CR₁;    -   X₂ is N;

X₃ is CR₄;

X₄ is CR₇;

X₆ is CR₉;

R₁ is selected from H, ester, halo, and CN;

R₃ is alkoxy;

R₄ is H;

-   -   R₅ is selected from H, alkynyl, —NR₁₀R₁₁, and —OR₁₁, each of        which is independently substituted with 0, 1, or 2 R₁₂, and R₁₂        is amino, alkoxy, or heterocyclyl; or when R₅ is —NR₁₀R₁₁, then        R₁₀ and R₁₁ can be taken together with the nitrogen atom to        which they are attached to form a heterocyclyl or heteroaryl        group, each of which is substituted with 1 R₁₂, and R₁₂ is alkyl        or amino;

R₆ is H;

R₇ is selected from H and alkoxy;

R₈ is selected from H and alkyl;

R₉ is selected from H, heterocyclyl, and aryl;

R₁₀ and R₁₁ are each independently alkyl, each of which is independentlysubstituted with 0, 1, or 2 R₁₂, and R₁₂ is amino, alkoxy, orheterocyclyl.

In some embodiments, the compound of Formula I can have the followingaspects:

A is selected from

-   -   X₁ is CR₁;    -   X₂ is N;

X₃ is CR₄;

-   -   X₄ is selected from N and CR₇;

X₆ is CR₉;

R₁ is selected from H, alkyl, and ester;

R₃ is alkoxy;

R₄ is H;

R₅ is selected from —NR₁₀R₁₁ and —OR₁₁.

R₆ is H;

R₇ is alkoxy;

R₈ is selected from H and alkyl;

R₉ is selected from H, aryl, and heteroaryl, each of which issubstituted with 0 or 1 R₁₂, and R₁₂ is halo;

R₁₀ is alkyl; and

R₁₁ is alkyl substituted with one R₁₂, and R₁₂ is substituted withalkoxy, amino or heterocyclyl.

In other embodiments, the compound of Formula I can have the followingaspects:

A is selected from

X₁ is CR₁;

X₂ is N;

X₃ is CR₄;

X₄ is CR₇;

X₆ is CR₉;

R₁ is selected from H, ester, amido, halo, and CN;

R₃ is alkoxy;

R₄ is H;

-   -   R₅ is selected from H, alkynyl, —NR₁₀R₁₁, and —OR₁₁, each of        which is independently substituted with 0, 1, or 2 R₁₂, and R₁₂        is amino, alkoxy, or heterocyclyl; or when R₅ is —NR₁₀R₁₁, then        R₁₀ and R₁₁ can be taken together with the nitrogen atom to        which they are attached to form a heterocyclyl or heteroaryl        group, each of which is substituted with 1 R₁₂, and R₁₂ is alkyl        or amino;

R₆ is H;

R₇ is selected from H and alkoxy;

R₈ is alkyl;

R₉ is selected from H and aryl substituted with 2 R₁₂, and R₁₂ is alkoxyor halo; and

R₁₀ and R₁₁ are each independently alkyl, each of which is independentlysubstituted with 0, 1, or 2 R₁₂, and R₁₂ is amino, alkoxy, orheterocyclyl.

Provided herein are compounds of Formula I selected from:

-   N-(3-((5-chloro-4-(6-(2-(pyrrolidin-1-yl)ethoxy)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;-   N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)ethoxy)-4-methoxyphenyl)acrylamide;-   N-(3-((5-cyano-4-(1-methyl-6-(2-(1-methylpyrrolidin-2-yl)ethoxy)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;-   N-(2-((2-(dimethylamino)ethyl)(methyl)-amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-5-(N-methylisobutyramido)-pyrimidin-2-yl)amino)phenyl)acrylamide;-   N-(3-((5-cyano-4-(1-methyl-6-(2-(pyrrolidin-1-yl)ethoxy)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;-   N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((5-isobutyramido-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;-   N-(3-((5-cyano-4-(6-(3-(dimethylamino)propoxy)-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;-   N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide;-   N-(4-methoxy-2-(methyl(2-(methylamino)ethyl)amino)-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide;-   N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide;    and-   N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-2-phenyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide;

or a pharmaceutically acceptable form thereof.

Provided herein are compounds of Formula I selected from:

-   N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-2-phenyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide;-   Sec-butyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Isobutyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   isopropyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1H-indol-1-yl)pyrimidine-5-carboxylate;-   N-(5-((4-(1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;-   isopropyl    2-((5-acrylamido-2-methoxy-4-(methyl(2-(methylamino)ethyl)-amino)phenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Isopropyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)methyl)amino)-2-methoxyphenyl)amino)-4-(7-methoxy-1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Cyclopropylmethyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Cyclobutyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   N-(5-((4-(2-(5-chloropyridin-3-yl)-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)methyl)amino)-4-methoxyphenyl)acrylamide;-   Isopropyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-5-carboxylate;-   Methyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Oxetan-3-yl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Isopropyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carboxylate;-   Isopropyl    2-((5-acrylamido-2-methoxy-4-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Ethyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Isopropyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;    and-   Isopropyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)methyl)amino)-2-methoxyphenyl)amino)-4-(1H-indol-3-yl)pyrimidine-5-carboxylate;-   Methyl    2-((5-acrylamido-2-methoxy-4-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)amino)-41-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;    and-   N-(5-((4-(2-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;

or a pharmaceutically acceptable form thereof.

Provided herein are compounds of Formula I selected from:

-   N-(3-((5-cyano-4-(1-methyl-6-((1-methylpyrrolidin-2-yl)methoxy)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;-   N-(3-((5-chloro-4-(1-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;-   isopropyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1H-indol-1-yl)pyrimidine-5-carboxylate;-   N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-5-pivalamidopyrimidin-2-yl)amino)phenyl)acrylamide;-   N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide;    and-   N-(5-((4-(2-(3-chlor-4-(pyridin-2-ylmethoxy)phenyl)-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;

or a pharmaceutically acceptable form thereof.

In another aspect, provided herein are compounds of Formula I

wherein:

A is selected from

-   -   X₁ is selected from

X₂ is selected from N and CR₂;

X₃ is selected from N and CR₄;

each X₄ is independently selected from N and CR₇;

-   -   X₅ is selected from N and CR₈;

X₆ is selected from N and CR₉;

-   -   each R₁ is independently selected from alkyl, alkenyl, alkynyl,        cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which is        substituted with 0, 1, 2, or 3 R₁₂;    -   R₁′ is selected from H and alkyl, each of which is substituted        with 0, 1, 2, or 3 R₁₂;    -   R₂, R₃, and R₄ are each independently selected from H, alkyl,        alkoxy, halo, CN, and NO₂, each of which is substituted with 0,        1, 2, or 3 R₁₂;    -   R₅ is selected from H, alkyl, alkenyl, alkynyl, —NR₁₀R₁₁, —OR₁₁,        and —SR₁₁, each of which is independently substituted with 0, 1,        2, or 3 R₁₂; or when R₅ is —NR₁₀R₁₁, then R₁₀ and R₁₁ can be        taken together with the nitrogen atom to which they are attached        to form a heterocyclyl or heteroaryl group, each of which is        substituted with 0, 1, 2, or 3 R₁₂;    -   R₄ and R₅ can be taken together with the carbon atoms to which        they are attached to form a cycloalkyl, heterocyclyl, aryl, or        heteroaryl group, each of which is substituted with 0, 1, 2, or        3 R₁₂;    -   R₆ is selected from H, acyl, alkyl, amino, halo, CN, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl, each of which is        substituted with 0, 1, 2, or 3 R₁₂;    -   each R₇ is independently selected from H, alkyl, alkenyl,        alkynyl, alkoxy, amido, amino, carbonyl, ester, halo, CN, and        NO₂, each of which is substituted with 0, 1, 2, or 3 R₁₂; and        wherein any two adjacent R₇ groups can be taken together with        the carbon atoms to which they are attached to form a        cycloalkyl, heterocyclyl, aryl, or heteroaryl ring, each of        which is substituted with 0, 1, 2, or 3 R₁₂;    -   R₈ is selected from H, acyl, alkyl, amido, amino, carbamate,        carbonyl, and urea, each of which is substituted with 0, 1, 2,        or 3 R₁₂;    -   R₉ is selected from H, alkyl, alkenyl, alkynyl, alkoxy, amino,        amido, ester, halo, CN, NO₂, cycloalkyl, heterocyclyl, aryl, and        heteroaryl, each of which is substituted with 0, 1, 2, or 3 R₁₂;    -   each R₁₀ and R₁₁ are independently selected from H, acyl, alkyl,        carbonyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl,        each of which is independently substituted with 0, 1, 2, or 3        R₁₂; and

each R₁₂ is independently selected from acyl, alkyl, alkenyl, alkynyl,alkoxy, aryloxy, alkoxycarbonyl, amido, amino, carbonate, carbamate,carbonyl, ester, halo, CN, NO₂, hydroxyl, phosphate, phosphonate,phosphinate, phosphine oxide, urea, cycloalkyl, heterocycloalkyl, aryl,and heteroaryl.

The following embodiments apply to any and all compounds of Formula I,where X₁ is

including, but not limited to, Formulae Aa, Ab, Ac, Ad, Ae, Ba, Bb, Bc,Bd, Be, Bf, Bg, and Bh.

In some embodiments, X₁ can be

In further embodiments, X₁ can be

and R₁ can be selected from alkyl, cycloalkyl, heterocyclyl, aryl andheteroaryl, each of which is substituted with 0 or 1 R₁₂. In otherembodiments, X₁ can be

and R₁ can be alkyl substituted with 0 or 1 R₁₂. In other embodiments,X₁ can be

and R₁ can be cycloalkyl substituted with 0 or 1 R₁₂. In otherembodiments, X₁ can be

and R₁ can be heterocyclyl substituted with 0 or 1 R₁₂.

In other embodiments, X₁ can be

In some embodiments, X₁ can be

R₁′ can be H, and R₁ can be alkyl substituted with 0 or 1 R₁₂. In someembodiments, X₁ can be

R₁′ can be alkyl, and R₁ can be alkyl substituted with 0 or 1 R₁₂. Insome embodiments, X₂ can be N. In other embodiments, X₂ can be CR₂,where R₂ is H. In some embodiments, X₁ can be N, and X₂ can be N. Insome embodiments, X₁ can be CR₁, and X₂ can be N.

In other embodiments, X₁ can be

and X₂ can be CR₂, where R₂ is H. In further embodiments, X₁ can be

and X₂ can be CR₂, where R₂ is H. In some embodiments, X₃ can be N. Inother embodiments, X₃ can be CR₄, where R₄ is H.In some embodiments, X₁ can be

X₂ can be N, and X₃ can be N. In some embodiments, X₁ can be

X₂ can be N, and X₃ can be CR₄, where R₄ is H. In further embodiments,X₁ can be

X₂ can be N, and X₃ can be N. In some embodiments, X₁ can be

X₂ can be N, and X₃ can be CR₄, where R₄ is H.

In some embodiments, X₁ can be selected from

In other embodiments, X₁ can be selected from

In further embodiments X₁ can be selected from

In other embodiments, the X₁ can be selected from

In further embodiments, X₁ can be selected from

In some embodiments, the compound of Formula I can have the followingaspects:

A is selected from

-   -   X₁ is

-   -   X₂ is N;    -   X₃ is CR₄;    -   R₁ is selected from alkyl and heterocyclyl;    -   R₃ is alkoxy;    -   R₄ is H;    -   R₅ is —NR₁₀R₁₁;    -   R₆ is H;    -   R₈ is alkyl;    -   R₁₀ is alkyl, and    -   R₁₁ is alkyl substituted with one R₁₂, and R₁₂ is amino or        heterocyclyl.

In some embodiments, the compound of Formula I can have the followingaspects:

A is selected from

-   -   X₁ is

-   -   X₂ is N;    -   X₃ is CR₄;    -   X₄ is selected from N and CR₇;    -   R₁ is alkyl, cycloalkyl, and heterocyclyl;    -   R₃ is alkoxy;    -   R₄ is H;    -   R₅ is —NR₁₀R₁₁;    -   R₆ is H;    -   R₇ is selected from H and alkoxy;    -   R₈ is selected from H and alkyl;    -   R₁₀ is alkyl, and    -   R₁₁ is alkyl substituted with one R₁₂, and R₁₂ is amino or        heterocyclyl.

In some embodiments, the compound of Formula I can have the followingaspects:

A is selected from

-   -   X₁ is selected from

-   -   X₂ is N;    -   X₃ is CR₄;    -   X₄ is selected from N and CR₇;    -   R₁ is selected from alkyl, cycloalkyl, and heterocyclyl;    -   R₁′ is H;    -   R₃ is alkoxy;    -   R₄ is H;    -   R₅ is selected from —NR₁₀R₁₁ and —OR₁₁;    -   R₆ is H;    -   R₇ is selected from H and alkoxy;    -   R₈ is selected from H and alkyl;    -   R₁₀ is alkyl, and    -   R₁₁ is alkyl substituted with one R₁₂, and R₁₂ is amino or        heterocyclyl.

In further embodiments, the compound of Formula I can have the followingaspects:

A is selected from

-   -   X₁ is selected from

-   -   X₂ is N;    -   X₃ is CR₄;    -   X₄ is N;    -   R₁ is alkyl;    -   R₁′ is H;    -   R₃ is alkoxy;    -   R₄ is H;    -   R₅ is —NR₁₀R₁₁;    -   R₆ is H;    -   R₈ is selected from H and alkyl;    -   R₁₀ is alkyl, and    -   R₁₁ is alkyl substituted with one R₁₂, and R₁₂ is amino or        heterocyclyl.

Provided herein are compounds of Formula I selected from:

-   Sec-butyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Isobutyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Isopropyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)methyl)amino)-2-methoxyphenyl)amino)-4-(7-methoxy-1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Cyclopropylmethyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((5-isobutyramido-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;-   Cyclobutyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Isopropyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-5-carboxylate;-   Methyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Oxetan-3-yl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Isopropyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carboxylate;-   N-(2-((2-(dimethylamino)ethyl)(methyl)-amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-5-(N-methylisobutyramido)-pyrimidin-2-yl)amino)phenyl)acrylamide;-   N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-5-pivalamidopyrimidin-2-yl)amino)phenyl)acrylamide;-   Isopropyl    2-((5-acrylamido-2-methoxy-4-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Ethyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Isopropyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1H-indol-1-yl)pyrimidine-5-carboxylate;-   Isopropyl    2-((5-acrylamido-2-methoxy-4-(methyl(2-(methylamino)ethyl)-amino)phenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Isopropyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Isopropyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1H-indol-3-yl)pyrimidine-5-carboxylate;    and-   Methyl    2-((5-acrylamido-2-methoxy-4-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;

or a pharmaceutically acceptable form thereof.

In another aspect, provided herein are compounds of Formula I

wherein:

-   -   A is

-   -   X₁ is

-   -   X₂ is N;    -   X₃ is CR₄;    -   R₁ is alkyl;    -   R₃ is alkoxy;    -   R₄ is H;    -   R₅ is —NR₁₀R₁₁    -   R₆ is H;    -   R₁₀ is alkyl, and    -   R₁₁ is alkyl substituted with one R₁₂, and R₁₂ is heterocyclyl.

Provided herein are compounds of Formula I, such as Isopropyl(R)-2-((5-(acryloyl-2-azanyl)-2-methoxy-4-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)-2-azanyl)-4-(benzofuran-3-yl)pyrimidine-5-carboxylate,or a pharmaceutically acceptable form thereof.

In another aspect, provided herein are compounds of Formula I

wherein:

-   -   A is

-   -   X₁ is

-   -   X₂ is N;    -   X₃ is CR₄;    -   R₁ is alkyl;    -   R₃ and R₄ are taken together with the carbon atoms to which they        are attached to form a cycloalkyl or heterocyclyl group;    -   R₅ is —NR₁₀R₁₁    -   R₆ is H;    -   R₁₀ is alkyl, and    -   R₁₁ is alkyl substituted with one R₁₂, and R₁₂ is amino.

Exemplary compounds of Formula I include, but are not limited to,

Further provided herein are compounds of Formula I, such as

In some embodiments, the compound of Formula I can be selected from

Provided herein are compounds of Formula I, such as

wherein R₃ is selected from alkyl, alkoxy, cyano and halo. In someembodiments, R₃ is selected from methyl, ethyl, propyl, methoxy, ethoxy,propoxy, fluoro, chloro and CN.

In some embodiments, X₃ is N and R₃ is alkoxy. In other embodiments, X₃is CR₄, and R₄ is selected from alkyl and halo, such as methyl, chloro,and fluoro. Exemplary compounds are given below:

Provided herein are compounds of Formula I where R₅ is selected from thefollowing amino groups:

where R₅ is selected from

where n is 0-4.

In some embodiments, the compounds described herein can have a molecularweight of less than about 800, less than about 700, less than about 600,or less than about 500 mass units (not including the weight of anysolvate, or of any counter-ion in the case of a salt).

Provided herein are compounds of Formula I selected from:

-   Isopropyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indazol-3-yl)pyrimidine-5-carboxylate;-   N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indazol-3-yl)-5-propionamidopyrimidin-2-yl)amino)phenyl)acrylamide;-   Isopropyl    (R)-2-((5-acrylamido-2-methoxy-4-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)amino)-4-(1H-indol-1-yl)pyrimidine-5-carboxylate;-   Isopropyl    (R)-2-((5-acrylamido-2-methoxy-4-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)amino)-4-(benzofuran-3-yl)pyrimidine-5-carboxylate;-   Methyl    (R)-2-((5-acrylamido-2-methoxy-4-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)amino)-4-(1H-indol-1-yl)pyrimidine-5-carboxylate;-   Isopropyl    (R)-2-((5-acrylamido-2-methoxy-4-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)amino)-4-(1H-indol-3-yl)pyrimidine-5-carboxylate;-   Ethyl    (R)-2-((5-acrylamido-2-methoxy-4-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Isopropyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)methyl)amino)-2-methoxyphenyl)amino)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carboxylate;-   Isopropyl    2-((5-acrylamido-4-(2-(dimethylamino)ethoxy)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Methyl    2-((5-acrylamido-4-(3-(dimethylamino)prop-1-yn-1-yl)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Methyl    2-((5-acrylamido-4-(3-(dimethylamino)propyl)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;    and-   N-(5-((4-(1-(2-amino-2-oxoethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)methyl)amino)-4-methoxyphenyl)acrylamide;-   or a pharmaceutically acceptable form thereof.-   Provided herein are compounds of Formula I selected from:-   N-(5-((4-(1-(2-amino-2-oxoethyl)-1H-indol-3-yl)-5-ethylpyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;-   N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((5-ethyl-4-(1-(2-(methylamino)-2-oxoethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;-   Methyl    2-((5-acrylamido-4-fluoro-2-methoxyphenyl)amino)-4-(1-(dimethylamino)-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Isopropyl    2-((5-acrylamido-2-methoxy-4-(methyl(2-(methylamino)ethyl)-amino)phenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Isopropyl    2-((5-acrylamido-2-methoxy-4-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyrimidine-3-yl)pyrimidine-5-carboxylate;-   Methyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-(dimethylamino)-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Isopropyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)methyl)amino)-2-methoxyphenyl)amino)-4-(1-ethyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Isopropyl    4-(1-acetyl-1H-indol-3-yl)-2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidine-5-carboxylate;-   Isopropyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidine-5-carboxylate;    and-   Methyl    3-(2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-4-carboxylate;

or a pharmaceutically acceptable form thereof.

Provided herein are compounds of Formula I selected from:

-   Methyl    3-(2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-5-carboxylate;-   Methyl    3-(2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-6-carboxylate;-   Methyl    3-(2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-6-carboxylate;-   Isopropyl    3-(2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-6-carboxylate;-   Isopropyl    3-(2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-7-carboxylate;-   Methyl    3-(2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-2-carboxylate;-   Isopropyl    3-(2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-2-carboxylate;-   N-(5-((4-(2-cyano-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethylmethyl)amino)-4-methoxyphenyl)acrylamide;-   N-(5-((4-(6-cyano-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethylmethyl)amino)-4-methoxyphenyl)acrylamide;    and-   3-(2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-2-carboxamide;

or a pharmaceutically acceptable form thereof.

Provided herein are compounds of Formula I selected from:

-   3-(2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-N,1-dimethyl-1H-indole-2-carboxamide;-   3-(2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-N,N,1-trimethyl-1H-indole-2-carboxamide;-   3-(2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-N-(2-methoxyethyl)-1-methyl-1H-indole-2-carboxamide;-   Isopropyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)methyl)amino)-2-methoxyphenyl)amino)-4-(imidazo[1,2-a]pyridin-3-yl)pyrimidine-5-carboxylate;-   N-(2-((2-(dimethylamino)ethyl)(methyl)amino)₄-methoxy-5-((4-(1-methyl-6-(1-methyl-1H-pyrazol-4-yl)-¹H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide;-   N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((5-(dimethylphosphoryl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide;-   Isopropyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)methyl)amino)-2-methoxyphenyl)amino)-(3-methyl-1H-indol-1-yl)pyrimidine-5-carboxylate;-   N-(5-((5-cyano-4-(1-methyl-1H-indazol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide;-   N-(2-((2-(dimethylamino)ethyl(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-5-(3-methylureido)pyrimidin-2-yl)amino)phenyl)acylamide;    and-   N-(2-((2-(dimethylamino)ethylmethyl)amino)-4-methoxy-5-((4-(1-methyl-2-((2-oxoazetidin-1-yl)methyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide;-   or a pharmaceutically acceptable form thereof.-   Provided herein are compounds of Formula I selected from:-   Methyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Isopropyl 2-((5    acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Isopropyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)methy)amino)-2-methoxyphenyl)amino)-4-(1H-indol-1-yl)pyrimidine-5-carboxylate;-   Isopropyl    2-((5-acrylamido-2-methoxy-4-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Isobutyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Isopropyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)methy)amino)-2-methoxyphenyl)amino)-4-(7-methoxy-1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;-   Isopropyl    2-((5-acrylamido-4-((2-(dimethylamino)ethyl)methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carboxylate;-   N-(2,4-dimethoxy-5-((4-(1-methyl-1H-indol-3-yl)-5-pivalamidopyrimidin-2-yl)amino)phenyl)acrylamide;    and-   Isopropyl    2-((5-acrylamido-2-methoxy-4-(methyl(2-(methylamino)ethyl)-amino)phenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate;

or a pharmaceutically acceptable form thereof.

Provided herein is the compound Methyl2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylateor a pharmaceutically acceptable form thereof.

Provided herein is the compound Isopropyl2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)₄-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylateor a pharmaceutically acceptable form thereof.

Provided herein is the compound Isopropyl2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1H-indol-1-yl)pyrimidine-5-carboxylateor a pharmaceutically acceptable form thereof.

Provided herein is the compound Isopropyl2-((5-acrylamido-2-methoxy-4-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylateor a pharmaceutically acceptable form thereof.

Provided herein is the compound Isopropyl2-((5-acrylamido-4-((2-(dimethylamino)ethyl)methyl)amino)-2-methoxyphenyl)amino)₄-(7-methoxy-1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylateor a pharmaceutically acceptable form thereof.

Provided herein is the compound Isopropyl2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)₄-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carboxylateor a pharmaceutically acceptable form thereof.

Provided herein is the compoundN-(2,4-dimethoxy-5-((4-(1-methyl-1H-indol-3-yl)-5-pivalamidopyrimidin-2-yl)amino)phenyl)acrylamideor a pharmaceutically acceptable form thereof.

Provided herein is the compound Isopropyl2-((5-acrylamido-2-methoxy-4-(methyl(2-(methylamino)ethyl)-amino)phenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylateor a pharmaceutically acceptable form thereof.

Activity

As used herein, the term “mutant EGFR” refers to epidermal growth factorreceptor having one or more mutations in any of its exons and includes,but is not limited to, EGFR having one or more mutations in the exon 20domain. Exon 20 insertion mutations include, but are not limited to, ASVand NPG. Mutant EGFR also includes the exon 20 T790M gatekeeper pointmutation. The T790M mutation can occur in combination with one or moreother mutations (including insertions, deletions and point mutations) inany EGFR exon. Non-limiting exemplary mutation combinations include theT790M gatekeeper mutation along with the exon 19 (delE746_A750) mutation(DT) and the T790M gatekeeper mutation along with the L858R mutation(LT) in exon 21. The term “mutant EGFR” is also inclusive of mutationsin exons that are not exon 20. Examples include, but are not limited to,the exon 19 (delE746_A750) mutation (D) and the exon 21 point mutationL858R (L).

As used herein, the term “exon 20 mutant EGFR” refers to one or more ofthe known exon 20 mutations, such as ASV, NPG, and T790M. In someembodiments, the exon 20 mutation can be ASV. In another embodiment, theexon 20 mutation can be NPG. In some embodiments, the exon 20 mutationcan be T790M. In some instances, the T790M mutation can be combined withone or more other EGFR mutations, such as D and L, to give the DT and LTmutations.

As used herein, the term “mutant HER2” refers to human epidermal growthfactor receptor 2 having one or more mutations in any of its exons andincludes, but is not limited to, HER2 having one or more mutations inthe exon 20 domain (“exon 20 mutant HER2”). Exon 20 insertion mutationsinclude, but are not limited to, YVMA. Exon 20 point mutations include,but are not limited to G776M.

In some embodiments, one or more compounds described herein bind toEGFR. In some embodiments, one or more compounds described herein bindto EGFR having one or more mutations (e.g., bind selectively). In someembodiments, the IC₅₀ of a subject compound for mutant EGFR inhibitioncan be less than about 100 nM, less than about 50 nM, less than about 10nM, less than about 1 nM, less than about 0.5 nM, or less than about 1pM.

In some embodiments, the IC₅₀ of a subject compound for mutant EGFRhaving one or more mutations in exon 20 can be less than about 100 nM,less than about 50 nM, less than about 10 nM, less than about 1 nM, lessthan about 0.5 nM, or less than about 1 pM. In some embodiments, theIC₅₀ value can be less than about 1 μM, less than about 500 nM, or lessthan about 250 nM. In some embodiments, the mutant EGFR has one or moreof the following insertions in the exon 20 domain: ASV or NPG. In otherembodiments, the mutant EGFR has either or both of the DT and/or LTmutations.

In some embodiments, the compounds disclosed herein inhibit EGFR, or anexon 20 mutant thereof, with an IC₅₀ value at least about 10 timeslower, at least about 50 times lower, at least about 100 times lower, orat least about 500 times lower than the IC₅₀ of another tyrosine kinase.In some embodiments, non-limiting exemplary compounds exhibit one ormore inhibitory activities disclosed herein. For example, one or moresubject compounds bind with greater affinity to exon 20 mutant EGFR ascompared to wild-type EGFR.

In some embodiments, the inhibitory activity of compounds disclosedherein against mutant EGFR can be greater than the activity of otherknown inhibitors. For example, disclosed compounds can inhibit mutantEGFR at least as well, about 2 times more potently, or about 10 timesmore potently as erlotinib or gefitinib.

In some embodiments, one or more compounds described herein bind toHER2. In some embodiments, one or more compounds described herein bindto HER2 having one or more mutations (e.g., bind selectively). In someembodiments, the IC₅₀ of a subject compound for mutant HER2 inhibitioncan be less than about 100 nM, less than about 50 nM, less than about 10nM, less than about 1 nM, less than about 0.5 nM, or less than about 1pM.

In some embodiments, the IC₅₀ of a subject compound for mutant HER2having one or more mutations in exon 20 can be less than about 100 nM,less than about 50 nM, less than about 10 nM, less than about 1 nM, lessthan about 0.5 nM, or less than about 1 pM. In some embodiments, theIC₅₀ value can be less than about 1 μM, less than about 500 nM, or lessthan about 250 nM. In some embodiments, the mutant HER2 has the YVMAinsertion in the exon 20 domain.

In some embodiments, the compounds disclosed herein inhibit HER2, or anexon 20 mutant thereof, with an IC₅₀ value at least about 10 timeslower, at least about 50 times lower, at least about 100 times lower, orat least about 500 times lower than the IC₅₀ of another tyrosine kinase.In some embodiments, non-limiting exemplary compounds exhibit one ormore inhibitory activities disclosed herein. For example, one or moresubject compounds bind with greater affinity to exon 20 mutant HER2 ascompared to wild-type EGFR. In some embodiments, the inhibitory activityof compounds disclosed herein against mutant HER2 can be greater thanthe activity of other known inhibitors.

In some embodiments, the compounds are also useful as standards andreagents for characterizing various kinases, including, but not limitedto, EGFR family kinases, as well as for studying the role of suchkinases in biological and pathological phenomena; for studyingintracellular signal transduction pathways mediated by such kinases, forthe comparative evaluation of new kinase inhibitors; and for studyingvarious cancers in cell lines and animal models.

Pharmaceutical Compositions

In some embodiments, provided herein are pharmaceutical compositionscomprising one or more compounds as disclosed herein, or apharmaceutically acceptable form thereof (e.g., pharmaceuticallyacceptable salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives), and one or more pharmaceuticallyacceptable excipients, carriers, including inert solid diluents andfillers, diluents, including sterile aqueous solution and variousorganic solvents, permeation enhancers, solubilizers and adjuvants. Insome embodiments, a pharmaceutical composition described herein includesa second active agent such as an additional therapeutic agent, (e.g., achemotherapeutic).

As described herein, the disclosed compositions comprise a disclosedcompound together with a pharmaceutically acceptable carrier, which, asused herein, includes any and all solvents, diluents, or other vehicle,dispersion or suspension aids, surface active agents, isotonic agents,thickening or emulsifying agents, preservatives, solid binders,lubricants and the like, as suited to the particular dosage formdesired. Except insofar as any conventional carrier medium isincompatible with the compounds provided herein, such as by producingany undesirable biological effect or otherwise interacting in adeleterious manner with any other component(s) of the pharmaceuticalcomposition, the carrier is contemplated to be within the scope of thisdisclosure.

1. Formulations

Pharmaceutical compositions can be specially formulated foradministration in solid or liquid form, including those adapted for thefollowing: oral administration, for example, drenches (aqueous ornon-aqueous solutions or suspensions), tablets (e.g., those targeted forbuccal, sublingual, and systemic absorption), capsules, boluses,powders, granules, pastes for application to the tongue, andintraduodenal routes; parenteral administration, including intravenous,intraarterial, subcutaneous, intramuscular, intravascular,intraperitoneal or infusion as, for example, a sterile solution orsuspension, or sustained-release formulation; topical application, forexample, as a cream, ointment, or a controlled-release patch or sprayapplied to the skin; intravaginally or intrarectally, for example, as apessary, cream, stent or foam; sublingually; ocularly; pulmonarily;local delivery by catheter or stent; intrathecally, or nasally.

Examples of suitable aqueous and nonaqueous carriers which can beemployed in pharmaceutical compositions include water, ethanol, polyols(such as glycerol, propylene glycol, polyethylene glycol, and the like),and suitable mixtures thereof, vegetable oils, such as olive oil, andinjectable organic esters, such as ethyl oleate. Proper fluidity can bemaintained, for example, by the use of coating materials, such aslecithin, by the maintenance of the required particle size in the caseof dispersions, and by the use of surfactants.

These compositions can also contain adjuvants such as preservatives,wetting agents, emulsifying agents, dispersing agents, lubricants,and/or antioxidants. Prevention of the action of microorganisms upon thecompounds described herein can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It can also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form can be brought about by the inclusionof agents which delay absorption such as aluminum monostearate andgelatin.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound described herein and/or thechemotherapeutic with the carrier and, optionally, one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing into association a compound as disclosed herein withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Preparations for such pharmaceutical compositions are well-known in theart. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, WilliamG, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill,2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition,Churchill Livingston, N.Y., 1990; Katzung, ed., Basic and ClinicalPharmacology, Ninth Edition, McGraw Hill, 2003; Goodman and Gilman,eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGrawHill, 2001; Remington's Pharmaceutical Sciences, 20th Ed., LippincottWilliams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia,Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all ofwhich are incorporated by reference herein in their entirety. Exceptinsofar as any conventional excipient medium is incompatible with thecompounds provided herein, such as by producing any undesirablebiological effect or otherwise interacting in a deleterious manner withany other component(s) of the pharmaceutically acceptable composition,the excipient's use is contemplated to be within the scope of thisdisclosure.

In some embodiments, the concentration of one or more of the compoundsprovided in the disclosed pharmaceutical compositions can be less thanabout 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about40%, about 30%, about 20%, about 19%, about 18%, about 17%, about 16%,about 15%, about 14%, about 13%, about 12%, about 11%, about 10%, about9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about2%, about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%,about 0.04%, about 0.03%, about 0.02%, about 0.01%, about 0.009%, about0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about0.003%, about 0.002%, about 0.001%, about 0.0009%, about 0.0008%, about0.0007%, about 0.0006%, about 0.0005%, about 0.0004%, about 0.0003%,about 0.0002%, or about 0.0001% w/w, w/v or v/v.

In some embodiments, the concentration of one or more of the compoundsas disclosed herein can be greater than about 90%, about 80%, about 70%,about 60%, about 50%, about 40%, about 30%, about 20%, about 19.75%,about 19.50%, about 19.25% about 19%, about 18.75%, about 18.50%, about18.25%, about 18%, about 17.75%, about 17.50%, about 17.25%, about 17%,about 16.75%, about 16.50%, about 16.25%, about 16%, about 15.75%, about15.50%, about 15.25%, about 15%, about 14.75%, about 14.50%, about14.25%, about 14%, about 13.75%, about 13.50%, about 13.25%, about 13%,about 12.75%, about 12.50%, about 12.25%, about 12%, about 11.75%, about11.50%, about 11.25%, about 11%, about 10.75%, about 10.50%, about10.25%, about 10%, about 9.75%, about 9.50%, about 9.25%, about 9%,about 8.75%, about 8.50%, about 8.25%, about 8%, about 7.75%, about7.50%, about 7.25%, about 7%, about 6.75%, about 6.50%, about 6.25%,about 6%, about 5.75%, about 5.50%, about 5.25%, about 5%, about 4.75%,about 4.50%, about 4.25%, about 4%, about 3.75%, about 3.50%, about3.25%, about 3%, about 2.75%, about 2.50%, about 2.25%, about 2%, about1.75%, about 1.50%, about 1.25%, about 1%, about 0.5%, about 0.4%, about0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%,about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, about0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about0.005%, about 0.004%, about 0.003%, about 0.002%, about 0.001%, about0.0009%, about 0.0008%, about 0.0007%, about 0.0006%, about 0.0005%,about 0.0004%, about 0.0003%, about 0.0002%, or about 0.0001% w/w, w/v,or v/v. In some embodiments, the concentration of one or more of thecompounds as disclosed herein can be in the range from approximately0.0001% to approximately 50%, approximately 0.001% to approximately 40%,approximately 0.01% to approximately 30%, approximately 0.02% toapproximately 29%, approximately 0.03% to approximately 28%,approximately 0.04% to approximately 27%, approximately 0.05% toapproximately 26%, approximately 0.06% to approximately 25%,approximately 0.07% to approximately 24%, approximately 0.08% toapproximately 23%, approximately 0.09% to approximately 22%,approximately 0.1% to approximately 21%, approximately 0.2% toapproximately 20%, approximately 0.3% to approximately 19%,approximately 0.4% to approximately 18%, approximately 0.5% toapproximately 17%, approximately 0.6% to approximately 16%,approximately 0.7% to approximately 15%, approximately 0.8% toapproximately 14%, approximately 0.9% to approximately 12%,approximately 1% to approximately 10% w/w, w/v or v/v, v/v. In someembodiments, the concentration of one or more of the compounds asdisclosed herein can be in the range from approximately 0.001% toapproximately 10%, approximately 0.01% to approximately 5%,approximately 0.02% to approximately 4.5%, approximately 0.03% toapproximately 4%, approximately 0.04% to approximately 3.5%,approximately 0.05% to approximately 3%, approximately 0.06% toapproximately 2.5%, approximately 0.07% to approximately 2%,approximately 0.08% to approximately 1.5%, approximately 0.09% toapproximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v orv/v.

In some embodiments, the amount of one or more of the compounds asdisclosed herein can be equal to or less than about 10 g, about 9.5 g,about 9.0 g, about 8.5 g, about 8.0 g, about 7.5 g, about 7.0 g, about6.5 g, about 6.0 g, about 5.5 g, about 5.0 g, about 4.5 g, about 4.0 g,about 3.5 g, about 3.0 g, about 2.5 g, about 2.0 g, about 1.5 g, about1.0 g, about 0.95 g, about 0.9 g, about 0.85 g, about 0.8 g, about 0.75g, about 0.7 g, about 0.65 g, about 0.6 g, about 0.55 g, about 0.5 g,about 0.45 g, about 0.4 g, about 0.35 g, about 0.3 g, about 0.25 g,about 0.2 g, about 0.15 g, about 0.1 g, about 0.09 g, about 0.08 g,about 0.07 g, about 0.06 g, about 0.05 g, about 0.04 g, about 0.03 g,about 0.02 g, about 0.01 g, about 0.009 g, about 0.008 g, about 0.007 g,about 0.006 g, about 0.005 g, about 0.004 g, about 0.003 g, about 0.002g, about 0.001 g, about 0.0009 g, about 0.0008 g, about 0.0007 g, about0.0006 g, about 0.0005 g, about 0.0004 g, about 0.0003 g, about 0.0002g, or about 0.0001 g. In some embodiments, the amount of one or more ofthe compounds as disclosed herein can be more than about 0.0001 g, about0.0002 g, about 0.0003 g, about 0.0004 g, about 0.0005 g, about 0.0006g, about 0.0007 g, about 0.0008 g, about 0.0009 g, about 0.001 g, about0.0015 g, about 0.002 g, about 0.0025 g, about 0.003 g, about 0.0035 g.about 0.004 g, about 0.0045 g, about 0.005 g, about 0.0055 g, about0.006 g, about 0.0065 g, about 0.007 g, about 0.0075 g, about 0.008 g,about 0.0085 g, about 0.009 g, about 0.0095 g, about 0.01 g, about 0.015g, about 0.02 g, about 0.025 g, about 0.03 g, about 0.035 g, about 0.04g, about 0.045 g, about 0.05 g, about 0.055 g, about 0.06 g, about 0.065g, about 0.07 g, about 0.075 g, about 0.08 g, about 0.085 g, about 0.09g, about 0.095 g, about 0.1 g, about 0.15 g, about 0.2 g, about 0.25 g,about 0.3 g, about 0.35 g, about 0.4 g, about 0.45 g, about 0.5 g, about0.55 g, about 0.6 g, about 0.65 g, about 0.7 g, about 0.75 g, about 0.8g, about 0.85 g, about 0.9 g, about 0.95 g, about 1 g, about 1.5 g,about 2 g, about 2.5, about 3 g, about 3.5, about 4 g, about 4.5 g,about 5 g, about 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5 g,about 8 g, about 8.5 g, about 9 g, about 9.5 g, or about 10 g.

In some embodiments, the amount of one or more of the compounds asdisclosed herein can be in the range of about 0.0001-about 10 g, about0.0005-about 9 g, about 0.001-about 0.5 g, about 0.001-about 2 g, about0.001-about 8 g, about 0.005-about 2 g, about 0.005-about 7 g, about0.01-about 6 g, about 0.05-about 5 g, about 0.1-about 4 g, about0.5-about 4 g, or about 1-about 3 g.

1A. Formulations for Oral Administration

In some embodiments, provided herein are pharmaceutical compositions fororal administration containing a compound as disclosed herein, and apharmaceutical excipient suitable for oral administration. In someembodiments, provided herein are pharmaceutical compositions for oraladministration containing: (i) an effective amount of a disclosedcompound; optionally (ii) an effective amount of one or more secondagents; and (iii) one or more pharmaceutical excipients suitable fororal administration. In some embodiments, the pharmaceutical compositionfurther contains: (iv) an effective amount of a third agent.

In some embodiments, the pharmaceutical composition can be a liquidpharmaceutical composition suitable for oral consumption. Pharmaceuticalcompositions suitable for oral administration can be presented asdiscrete dosage forms, such as capsules, cachets, or tablets, or liquidsor aerosol sprays each containing a predetermined amount of an activeingredient as a powder or in granules, a solution, or a suspension in anaqueous or non-aqueous liquid, an oil-in-water emulsion, or awater-in-oil liquid emulsion. Such dosage forms can be prepared by anyof the methods of pharmacy, but all methods include the step of bringingthe active ingredient into association with the carrier, whichconstitutes one or more ingredients. In general, the pharmaceuticalcompositions are prepared by uniformly and intimately admixing theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product into the desiredpresentation. For example, a tablet can be prepared by compression ormolding, optionally with one or more accessory ingredients. Compressedtablets can be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with an excipient such as, but not limited to, a binder, alubricant, an inert diluent, and/or a surface active or dispersingagent. Molded tablets can be made by molding in a suitable machine amixture of the powdered compound moistened with an inert liquid diluent.

The tablets can be uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. Formulations for oral use can also be presented as hardgelatin capsules wherein the active ingredient can be mixed with aninert solid diluent, for example, calcium carbonate, calcium phosphateor kaolin, or as soft gelatin capsules wherein the active ingredient canbe mixed with water or an oil medium, for example, peanut oil, liquidparaffin or olive oil.

The present disclosure further encompasses anhydrous pharmaceuticalcompositions and dosage forms comprising an active ingredient, sincewater can facilitate the degradation of some compounds. For example,water can be added (e.g., about 5%) in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. Anhydrous pharmaceutical compositions and dosage forms can beprepared using anhydrous or low moisture containing ingredients and lowmoisture or low humidity conditions. For example, pharmaceuticalcompositions and dosage forms which contain lactose can be madeanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected. An anhydrouspharmaceutical composition can be prepared and stored such that itsanhydrous nature is maintained. Accordingly, anhydrous pharmaceuticalcompositions can be packaged using materials known to prevent exposureto water such that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastic or the like, unit dose containers,blister packs, and strip packs.

An active ingredient can be combined in an intimate admixture with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier can take a wide variety of formsdepending on the form of preparation desired for administration. Inpreparing the pharmaceutical compositions for an oral dosage form, anyof the usual pharmaceutical media can be employed as carriers, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents, and the like in the case of oral liquidpreparations (such as suspensions, solutions, and elixirs) or aerosols;or carriers such as starches, sugars, micro-crystalline cellulose,diluents, granulating agents, lubricants, binders, and disintegratingagents can be used in the case of oral solid preparations, in someembodiments without employing the use of lactose. In some embodiments,compounds can be admixed with lactose, sucrose, starch powder, celluloseesters of alkanoic acids, cellulose alkyl esters, talc, stearic acid,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate,polyvinylpyrrolidone, and/or polyvinyl alcohol for subsequentformulation. For example, suitable carriers include powders, capsules,and tablets, with the solid oral preparations. In some embodiments,tablets can be coated by standard aqueous or nonaqueous techniques.

Binders suitable for use in pharmaceutical compositions and dosage formsinclude, but are not limited to, corn starch, potato starch, or otherstarches, gelatin, natural and synthetic gums such as acacia, sodiumalginate, alginic acid, other alginates, powdered tragacanth, guar gum,cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate,carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixturesthereof.

Examples of suitable fillers for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

Disintegrants can be used in the pharmaceutical compositions as providedherein to provide tablets that disintegrate when exposed to an aqueousenvironment. Too much of a disintegrant can produce tablets which candisintegrate in the bottle. Too little can be insufficient fordisintegration to occur and can thus alter the rate and extent ofrelease of the active ingredient(s) from the dosage form. Thus, asufficient amount of disintegrant that is neither too little nor toomuch to detrimentally alter the release of the active ingredient(s) canbe used to form the dosage forms of the compounds disclosed herein. Theamount of disintegrant used can vary based upon the type of formulationand mode of administration, and can be readily discernible to those ofordinary skill in the art. About 0.5 to about 15 weight percent ofdisintegrant, or about 1 to about 5 weight percent of disintegrant, canbe used in the pharmaceutical composition. Disintegrants that can beused to form pharmaceutical compositions and dosage forms include, butare not limited to, agaragar, alginic acid, calcium carbonate,microcrystalline cellulose, croscarmellose sodium, crospovidone,polacrilin potassium, sodium starch glycolate, potato or tapioca starch,other starches, pre-gelatinized starch, other starches, clays, otheralgins, other celluloses, gums or mixtures thereof.

Lubricants which can be used to form pharmaceutical compositions anddosage forms include, but are not limited to, calcium stearate,magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol,mannitol, polyethylene glycol, other glycols, stearic acid, sodiumlauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil,cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, ormixtures thereof. Additional lubricants include, for example, a syloidsilica gel, a coagulated aerosol of synthetic silica, or mixturesthereof. A lubricant can optionally be added, in an amount of less thanabout 1 weight percent of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oraladministration, the active ingredient therein can be combined withvarious sweetening or flavoring agents, coloring matter or dyes and, forexample, emulsifying and/or suspending agents, together with suchdiluents as water, ethanol, propylene glycol, glycerin and variouscombinations thereof.

Surfactants which can be used to form pharmaceutical compositions anddosage forms include, but are not limited to, hydrophilic surfactants,lipophilic surfactants, and mixtures thereof. That is, a mixture ofhydrophilic surfactants can be employed, a mixture of lipophilicsurfactants can be employed, or a mixture of at least one hydrophilicsurfactant and at least one lipophilic surfactant can be employed.

A suitable hydrophilic surfactant can generally have an HLB value of atleast about 10, while suitable lipophilic surfactants can generally havean HLB value of or less than about 10. An empirical parameter used tocharacterize the relative hydrophilicity and hydrophobicity of non-ionicamphiphilic compounds is the hydrophilic-lipophilic balance (“HLB”value). Surfactants with lower HLB values are more lipophilic orhydrophobic, and have greater solubility in oils, while surfactants withhigher HLB values are more hydrophilic, and have greater solubility inaqueous solutions. Hydrophilic surfactants are generally considered tobe those compounds having an HLB value greater than about 10, as well asanionic, cationic, or zwitterionic compounds for which the HLB scale isnot generally applicable. Similarly, lipophilic (i.e., hydrophobic)surfactants are compounds having an HLB value equal to or less thanabout 10. However, HLB value of a surfactant is merely a rough guidegenerally used to enable formulation of industrial, pharmaceutical andcosmetic emulsions.

Hydrophilic surfactants can be either ionic or nonionic. Suitable ionicsurfactants include, but are not limited to, alkylammonium salts;fusidic acid salts; fatty acid derivatives of amino acids,oligopeptides, and polypeptides; glyceride derivatives of amino acids,oligopeptides, and polypeptides; lecithins and hydrogenated lecithins;lysolecithins and hydrogenated lysolecithins; phospholipids andderivatives thereof; lysophospholipids and derivatives thereof;carnitine fatty acid ester salts; salts of alkylsulfates; fatty acidsalts; sodium docusate; acylactylates; mono- and di-acetylated tartaricacid esters of mono- and di-glycerides; succinylated mono- anddi-glycerides; citric acid esters of mono- and di-glycerides; andmixtures thereof.

Within the aforementioned group, ionic surfactants include, by way ofexample: lecithins, lysolecithin, phospholipids, lysophospholipids andderivatives thereof; carnitine fatty acid ester salts; salts ofalkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono-and di-acetylated tartaric acid esters of mono- and di-glycerides;succinylated mono- and di-glycerides; citric acid esters of mono- anddi-glycerides; and mixtures thereof.

Ionic surfactants can be the Ionized forms of lecithin, lysolecithin,phosphatidykcholine, phosphatidylethanolamine, phosphatidylglycerol,phosphatidic acid, phosphatidylserine, lysophosphatidylcholine,lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidicacid, lysophosphatidylserine, PEG-phosphatidylethanolamine,PVP-phosphatidylethanolamine, lactylic esters of fatty acids,stearoyl-2-1actylate, stearoyl lactylate, succinylated monoglycerides,mono/diacetylated tartaric acid esters of mono/diglycerides, citric acidesters of mono/diglycerides, cholylsarcosine, caproate, caprylate,caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate,linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate,lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, andsalts and mixtures thereof.

Hydrophilic non-Ionic surfactants can include, but are not limited to,alkylglucosides; alkylmaltosides; alkylthioglucosides; laurylmacrogolglycerides; polyoxyalkylene alkyl ethers such as polyethyleneglycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethyleneglycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esterssuch as polyethylene glycol fatty acids monoesters and polyethyleneglycol fatty acids diesters; polyethylene glycol glycerol fatty acidesters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fattyacid esters such as polyethylene glycol sorbitan fatty acid esters;hydrophilic transesterification products of a polyol with at least onemember of glycerides, vegetable oils, hydrogenated vegetable oils, fattyacids, and sterols; polyoxyethylene sterols, derivatives, and analoguesthereof; polyoxyethylated vitamins and derivatives thereof;polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof;polyethylene glycol sorbitan fatty acid esters and hydrophilictransesterification products of a polyol with at least one member oftriglycerides, vegetable oils, and hydrogenated vegetable oils. Thepolyol can be glycerol, ethylene glycol, polyethylene glycol, sorbitol,propylene glycol, pentaerythritol, or a saccharide.

Other hydrophilic-non-ionic surfactants include, without limitation,PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32dilaurate, PEG-12 oleate, PEG-15 oleate. PEG-20 oleate, PEG-20 dioleate,PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate,PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryllaurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenatedcastor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitanlaurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearylether, tocopheryl PEG-100 succinate, PEG-24 cholesterol,polyglyceryl-10oleate, Tween 40, Tween 60, sucrose monostearate, sucrosemonolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG15-100 octyl phenol series, and poloxamers.

Suitable lipophilic surfactants include, by way of example only: fattyalcohols; glycerol fatty acid esters; acetylated glycerol fatty acidesters; lower alcohol fatty acids esters; propylene glycol fatty acidesters; sorbitan fatty acid esters; polyethylene glycol sorbitan fattyacid esters; sterols and sterol derivatives; polyoxyethylated sterolsand sterol derivatives; polyethylene glycol alkyl ethers; sugar esters;sugar ethers; lactic acid derivatives of mono- and di-glycerides;hydrophobic transesterification products of a polyol with at least onemember of glycerides, vegetable oils, hydrogenated vegetable oils, fattyacids and sterols; oil-soluble vitamins/vitamin derivatives; andmixtures thereof. Within this group, non-limiting examples of lipophilicsurfactants include glycerol fatty acid esters, propylene glycol fattyacid esters, and mixtures thereof, or are hydrophobictransesterification products of a polyol with at least one member ofvegetable oils, hydrogenated vegetable oils, and triglycerides.

In one embodiment, the pharmaceutical composition can include asolubilizer to ensure good solubilization and/or dissolution of acompound as provided herein and to minimize precipitation of thecompound. This can be especially important for pharmaceuticalcompositions for nonoral use, e.g., pharmaceutical compositions forinjection. A solubilizer can also be added to increase the solubility ofthe hydrophilic drug and/or other components, such as surfactants, or tomaintain the pharmaceutical composition as a stable or homogeneoussolution or dispersion.

Examples of suitable solubilizers include, but are not limited to, thefollowing: alcohols and polyols, such as ethanol, isopropanol, butanol,benzyl alcohol, ethylene glycol, propylene glycol, butanediols andisomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropyleneglycol, polyvinylalcohol, hydxoxypropyl methylcellulose and othercellulose derivatives, cyclodextrins and cyclodextrin derivatives;ethers of polyethylene glycols having an average molecular weight ofabout 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether(glycofurol) or methoxy PEG; amides and other nitrogen-containingcompounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam,N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esterssuch as ethyl propionate, tributylcitrate, acetyl triethylcitrate,acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate,ethyl butyrate, triacetin, propylene glycol monoacetate, propyleneglycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactoneand isomers thereof, β-butyrolactone and isomers thereof; and othersolubilizers known in the art, such as dimethyl acetamide, dimethylisosorbide, N-methylpyrrolidones, monooctanoin, diethylene glycolmonoethyl ether, and water.

Mixtures of solubilizers can also be used. Examples include, but notlimited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate,dimethylacetamide, N-methylpyrrolidone, N-hydxoxyethylpyrrolidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydxoxypropylcyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol,transcutol, propylene glycol, and dimethyl isosorbide. In someembodiments, solubilizers include sorbitol, glycerol, triacetin, ethylalcohol, PEG-400, glycofurol and propylene glycol.

The amount of solubilizer that can be included can vary with thecomposition. The amount of a given solubilizer can be limited to abioacceptable amount, which can be readily determined by one of skill inthe art. In some circumstances, it can be advantageous to includeamounts of solubilizers far in excess of bioacceptable amounts, forexample to maximize the concentration of the drug, with excesssolubilizer removed prior to providing the pharmaceutical composition toa subject using conventional techniques, such as distillation orevaporation. Thus, if present, the solubilizer can be in a weight ratioof about 10%, about 25%, about 50%, about 100%, or up to about 200% byweight, based on the combined weight of the drug, and other excipients.If desired, very small amounts of solubilizer can also be used, such asabout 5%, 2%, 1% or even less. Typically, the solubilizer can be presentin an amount of about 1% to about 100%, more typically about 5% to about25% by weight.

The pharmaceutical composition can further include one or morepharmaceutically acceptable additives and excipients. Such additives andexcipients include, without limitation, detackifiers, anti-foamingagents, buffering agents, polymers, antioxidants, preservatives,chelating agents, viscomodulators, tonicifiers, flavorants, colorants,oils, odorants, opacifiers, suspending agents, binders, fillers,plasticizers, lubricants, and mixtures thereof.

Exemplary preservatives can include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, alcoholpreservatives, acidic preservatives, and other preservatives. Exemplaryantioxidants include, but are not limited to, alpha tocopherol, ascorbicacid, acorbyl palmitate, butylated hydroxyanisole, butylatedhydroxytoluene, monothioglycerol, potassium metabisulfite, propionicacid, propyl gallate, sodium ascorbate, sodium bisulfite, sodiummetabisulfite, and sodium sulfite. Exemplary chelating agents includeethylenediaminetetraacetic acid (EDTA), citric acid monohydrate,disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malicacid, phosphoric acid, sodium edetate, tartaric acid, and trisodiumedetate. Exemplary antimicrobial preservatives include, but are notlimited to, benzalkonium chloride, benzethonium chloride, benzylalcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine,chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol,glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethylalcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.Exemplary antifungal preservatives include, but are not limited to,butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoicacid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodiumbenzoate, sodium propionate, and sorbic acid. Exemplary alcoholpreservatives include, but are not limited to, ethanol, polyethyleneglycol, phenol, phenolic compounds, bisphenol, chlorobutanol,hydroxybenzoate, and phenylethyl alcohol. Exemplary acidic preservativesinclude, but are not limited to, vitamin A, vitamin C, vitamin E,betacarotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid. Other preservatives include, but arenot limited to, tocopherol, tocopherol acetate, deteroxime mesylate,cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluene(BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ethersulfate (SLES), sodium bisulfite, sodium metabisulfite, potassiumsulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben,Germall 115, Germaben II, Neolone, Kathon, and Euxyl. In certainembodiments, the preservative can be an anti-oxidant. In otherembodiments, the preservative can be a chelating agent.

Exemplary oils include, but are not limited to, almond, apricot kernel,avocado, babassu, bergamot, black current seed, borage, cade, camomile,canola, caraway, camauba, castor, cinnamon, cocoa butter, coconut, codliver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose,fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop,isopropyl myristate, jojoba, kukni nut, lavandin, lavender, lemon,litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink,nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel,peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary,safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, sheabutter, silicone, soybean, sunflower, tea tree, thistle, tsubaki,vetiver, walnut, and wheat germ oils. Exemplary oils include, but arenot limited to, butyl stearate, caprylic triglyceride, caprictriglyceride, cyclomethicone, diethyl sebacate, dimethicone 360,isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol,silicone oil, and combinations thereof.

Oil/aqueous emulsion formulations can include an emulsifier, or it cancomprise a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. In some embodiments, a hydrophilicemulsifier can be included together with a lipophilic emulsifier whichacts as a stabilizer. In one embodiment, both an oil and a fat can beused. Together, the emulsifier(s) with or without stabilizer(s) createan emulsifying wax, and the wax together with the oil and fat form anemulsifying ointment base. This ointment base forms the oily dispersedphase of the cream formulations. Emulsifiers and emulsion stabilizerssuitable for use in the disclosed formulations include Tween 60, Span80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodiumlauryl sulfate, glyceryl distearate alone or with a wax, or othermaterials well known in the art. In some cases, the solubility of theactive compound in the oil(s) likely to be used in the pharmaceuticalemulsion formulations can be low. Straight or branched chain, mono- ordibasic alkyl esters can aid solubility, such as di-isoadipate, isocetylstearate, propylene glycol diester of coconut fatty acids, isopropylmyristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters can be used.These can be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

In addition, an acid or a base can be incorporated into thepharmaceutical composition to facilitate processing, to enhancestability, or for other reasons. Examples of pharmaceutically acceptablebases include amino acids, amino acid esters, ammonium hydroxide,potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate,aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesiumaluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite,magnesium aluminum hydroxide, diisopropytethylamine, ethanolamine,ethylenediamine, triethanolamine, triethylamine, triisopropanolamine,trimethylanine, tris(hydroxymethyl)aminomethane (TRIS) and the like.Also suitable are bases that are salts of a pharmaceutically acceptableacid, such as acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonicacid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearicacid, succinic acid, tannic acid, tartaric acid, thioglycolic acid,toluenesulfonic acid, uric acid, and the like. Salts of polyproticacids, such as sodium phosphate, disodium hydrogen phosphate, and sodiumdihydrogen phosphate can also be used. When the base is a salt, thecation can be any convenient and pharmaceutically acceptable cation,such as ammonium, alkali metals, alkaline earth metals, and the like.Examples can include, but not limited to, sodium, potassium, lithium,magnesium, calcium and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganicacids. Examples of suitable inorganic acids include hydrochloric acid,hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boricacid, phosphoric acid, and the like. Examples of suitable organic acidsinclude acetic acid, acrylic acid, adipic acid, alginic acid,alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boricacid, butyric acid, carbonic acid, citric acid, fatty acids, formicacid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbicacid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, parabromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid,salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid,thioglycolic acid, toluenesulfonic acid, uric acid and the like.

1B. Formulations for Parenteral Administration

In some embodiments, provided herein are pharmaceutical compositions forparenteral administration containing a compound as disclosed herein, andone or more pharmaceutical excipients suitable for parenteraladministration. In some embodiments, provided herein are pharmaceuticalcompositions for parenteral administration containing: (i) an effectiveamount of a disclosed compound; optionally (ii) an effective amount ofone or more second agents; and (iii) one or more pharmaceuticalexcipients suitable for parenteral administration. In some embodiments,the pharmaceutical composition further contains: (iv) an effectiveamount of a third agent.

The forms in which the disclosed pharmaceutical compositions can beincorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles. Aqueous solutions insaline are also conventionally used for injection. Ethanol, glycerol,propylene glycol, liquid polyethylene glycol, benzyl alcohol, and thelike (and suitable mixtures thereof), cyclodextrin derivatives, sodiumchloride, tragacanth gum, buffers, and vegetable oils can also beemployed.

Aqueous solutions in saline are also conventionally used for injection.Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and thelike (and suitable mixtures thereof), cyclodextrin derivatives, andvegetable oils can also be employed. The proper fluidity can bemaintained, for example, by the use of a coating, such as lecithin, forthe maintenance of the required particle size in the case of dispersionand by the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like.

In some embodiments, the active ingredient can also be administered byinjection as a composition with suitable carriers including saline,dextrose, or water, or with cyclodextrin (e.g., Captisol), cosolventsolubilization (e.g., propylene glycol) or micellar solubilization(e.g., Tween 80).

Sterile injectable solutions are prepared by incorporating a compound asdisclosed herein in the required amount in the appropriate solvent withvarious other ingredients as enumerated above, as appropriate, followedby filtered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the appropriateother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, certainmethods of preparation are vacuum-drying and freeze-drying techniqueswhich yield a powder of the active ingredient plus any additionalingredient from a previously sterile-filtered solution thereof.

The sterile injectable preparation can also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil can be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use. Injectable compositions can contain from about 0.1to about 5% w/w of a compound as disclosed herein.

1C. Formulations for Topical Administration

In some embodiments, provided herein are pharmaceutical compositions fortopical (e.g., transdermal) administration containing a compound asdisclosed herein, and one or more pharmaceutical excipients suitable fortopical administration. In some embodiments, provided herein arepharmaceutical compositions for topical administration containing: (i)an effective amount of a disclosed compound; optionally (ii) aneffective amount of one or more second agents; and (iii) one or morepharmaceutical excipients suitable for topical administration. In someembodiments, the pharmaceutical composition further contains: (iv) aneffective amount of a third agent.

Pharmaceutical compositions provided herein can be formulated intopreparations in solid, semi-solid, or liquid forms suitable for local ortopical administration, such as gels, water soluble jellies, linements,creams, lotions, suspensions, foams, powders, slurries, ointments,solutions, oils, pastes, suppositories, sprays, emulsions, salinesolutions, dimethylsulfoxide (DMSO)-based solutions. In general,carriers with higher densities are capable of providing an area with aprolonged exposure to the active ingredients. In contrast, a solutionformulation can provide more immediate exposure of the active ingredientto the chosen area. For example, an ointment formulation can have eithera paraffinic or a water-miscible base. Alternatively, the activeingredient can be formulated in a cream with an oil-in-water cream base.The aqueous phase of the cream base can include, for example at leastabout 30% w/w of a polyhydric alcohol such as propylene glycol,butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol andmixtures thereof.

The pharmaceutical compositions also can comprise suitable solid or gelphase carriers or excipients, which are compounds that allow increasedpenetration of, or assist in the delivery of, therapeutic moleculesacross the stratum corneum permeability barrier of the skin. There aremany of these penetration-enhancing molecules known to those trained inthe art of topical formulation. Examples of such carriers and excipientsinclude, but are not limited to, humectants (e.g., urea), glycols (e.g.,propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleicadd), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate),pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g.,menthol), amines, amides, alkanes, alkanols, water, calcium carbonate,calcium phosphate, various sugars, starches, cellulose derivatives,gelatin, and polymers such as polyethylene glycols.

Another exemplary formulation for use in the disclosed methods employstransdermal delivery devices (“patches”). Such transdermal patches canbe used to provide continuous or discontinuous infusion of a compound asprovided herein in controlled amounts, either with or without anotheragent. Patchs can be either of the reservoir and porous membrane type orof a solid matrix variety. In either case, the active agent can bedelivered continuously from the reservoir or microcapsules through amembrane into the active agent permeable adhesive, which is in contactwith the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent can be administered to the recipient. In the case ofmicrocapsules, the encapsulating agent can also function as themembrane.

The construction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art. See, e.g., U.S. Pat.Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches can be constructedfor continuous, pulsatile, or on demand delivery of pharmaceuticalagents.

Suitable devices for use in delivering intradermal pharmaceuticallyacceptable compositions described herein include short needle devicessuch as those described in U.S. Pat. Nos. 4,886,499; 5,190,521;5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and 5,417,662.Intradermal compositions can be administered by devices which limit theeffective penetration length of a needle into the skin, such as thosedescribed in PCT publication WO 99/34850 and functional equivalentsthereof. Jet injection devices which deliver liquid vaccines to thedermis via a liquidj et injector and/or via a needle which pierces thestratum corneum and produces a jet which reaches the dermis aresuitable. Jet injection devices are described, for example, in U.S. Pat.Nos. 5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189;5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335;5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880;4,940,460; and PCT publications WO97/37705 and WO 97/13537. Ballisticpowder/particle delivery devices which use compressed gas to acceleratevaccine in powder form through the outer layers of the skin to thedermis are suitable. Alternatively or additionally, conventionalsyringes can be used in the classical mantoux method of intradermaladministration.

Topically-administrable formulations can, for example, comprise fromabout 1% to about 10% (w/w) of a disclosed compound, although theconcentration of the compound of Formula I can be as high as thesolubility limit of the compound in the solvent. In some embodiments,topically-administrable formulations can, for example, include fromabout 0.001% to about 10% (w/w) compound, about 1% to about 9% (w/w)compound, such as from about 1% to about 8% (w/w), further such as fromabout 1% to about 7% (w/w), further such as from about 1% to about 6%(w/w), further such as from about 1% to about 5% (w/w), further such asfrom about 1% to about 4% (w/w), further such as from about 1% to about3% (w/w), further such as from about 1% to about 2% (w/w), and furthersuch as from about 0.1% to about 1% (w/w) compound. In some embodiments,the topical formulation includes about 0.1 mg to about 150 mgadministered one to four, such as one or two times daily. Formulationsfor topical administration can further comprise one or more of theadditional pharmaceutically acceptable excipients described herein.

1D. Formulations for Inhalation Administration

In some embodiments, provided herein are pharmaceutical compositions forinhalation administration containing a compound as disclosed herein, andone or more pharmaceutical excipients suitable for topicaladministration. In some embodiments, provided herein are pharmaceuticalcompositions for inhalation administration containing: (i) an effectiveamount of a disclosed compound; optionally (ii) an effective amount ofone or more second agents; and (iii) one or more pharmaceuticalexcipients suitable for inhalation administration. In some embodiments,the pharmaceutical composition further contains: (iv) an effectiveamount of a third agent.

Pharmaceutical compositions for inhalation or insufflation includesolutions and suspensions in pharmaceutically acceptable, aqueous ororganic solvents, or mixtures thereof and powders. The liquid or solidpharmaceutical compositions can contain suitable pharmaceuticallyacceptable excipients as described herein. For example, suitableexcipients include, but are not limited to, saline, benzyl alcohol andfluorocarbons. In some embodiments, the pharmaceutical compositions areadministered by the oral or nasal respiratory route for local orsystemic effect. Pharmaceutical compositions in pharmaceuticallyacceptable solvents can be nebulized by use of inert gases. Nebulizedsolutions can be inhaled directly from the nebulizing device or thenebulizing device can be attached to a face mask tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powderpharmaceutical compositions can be administered, e.g., orally ornasally, from devices that deliver the formulation in an appropriatemanner.

1E. Formulations for Ocular Administration

In some embodiments, provided herein are pharmaceutical compositions forophthalmic administration containing a compound as disclosed herein, andone or more pharmaceutical excipients suitable for ophthalmicadministration. Pharmaceutical compositions suitable for ocularadministration can be presented as discrete dosage forms, such as dropsor sprays each containing a predetermined amount of an activeingredient, a solution, or a suspension in an aqueous or non-aqueousliquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.Other administration forms include intraocular injection, intravitrealinjection, topically, or through the use of a drug eluting device,microcapsule, implant, or microfluidic device. In some cases, thecompounds as disclosed herein are administered with a carrier orexcipient that increases the intraocular penetrance of the compound suchas an oil and water emulsion with colloid particles having an oily coresurrounded by an interfacial film. It is contemplated that all localroutes to the eye can be used including topical, subconjunctival,periocular, retrobulbar, subtenon, intracameral, intravitreal,intraocular, subretinal, juxtascleral and suprachoroidal administration.Systemic or parenteral administration can be feasible including, but notlimited to, intravenous, subcutaneous, and oral delivery. An exemplarymethod of administration will be intravitreal or subtenon injection ofsolutions or suspensions, or intravitreal or subtenon placement ofbioerodible or non-bioerodible devices, or by topical ocularadministration of solutions or suspensions, or posterior juxtascleraladministration of a gel or cream formulation.

Eye drops can be prepared by dissolving the active ingredient in asterile aqueous solution such as physiological saline, bufferingsolution, etc., or by combining powder compositions to be dissolvedbefore use. Other vehicles can be chosen, as is known in the art,including, but not limited to: balance salt solution, saline solution,water soluble polyethers such as polyethyene glycol, polyvinyls, such aspolyvinyl alcohol and povidone, cellulose derivatives such asmethylcellulose and hydroxypropyl methylcellulose, petroleum derivativessuch as mineral oil and white petrolatum, animal fats such as lanolin,polymers of acrylic acid such as carboxypolymethylene gel, vegetablefats such as peanut oil and polysaccharides such as dextrans, andglycosaminoglycans such as sodium hyaluronate. In some embodiments,additives ordinarily used in the eye drops can be added. Such additivesinclude isotonizing agents (e.g., sodium chloride, etc.), buffer agent(e.g., boric acid, sodium monohydrogen phosphate, sodium dihydrogenphosphate, etc.), preservatives (e.g., benzalkonium chloride,benzethonium chloride, chlorobutanol, etc.), thickeners (e.g.,saccharide such as lactose, mannitol, maltose, etc.; e.g., hyaluronicacid or its salt such as sodium hyaluronate, potassium hyaluronate,etc.; e.g., mucopolysaccharide such as chondritin sulfate, etc.; e.g.,sodium polyacrylate, carboxyvinyl polymer, crosslinked polyacrylate,polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose,hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethylcellulose, hydroxypropyl cellulose or other agents known to thoseskilled in the art).

In some cases, the colloid particles include at least one cationic agentand at least one non-ionic surfactant such as a poloxamer, tyloxapol, apolysorbate, a polyoxyethylene castor oil derivative, a sorbitan ester,or a polyoxyl stearate. In some cases, the cationic agent can beselected from an alkylamine, a tertiary alkyl amine, a quaternaryammonium compound, a cationic lipid, an amino alcohol, a biguanidinesalt, a cationic compound or a mixture thereof. In some cases, thecationic agent can be a biguanidine salt such as chlorhexidine,polyaminopropyl biguanidine, phenformin, alkylbiguanidine, or a mixturethereof. In some cases, the quaternary ammonium compound can be abenzalkonium halide, lauralkonium halide, cetrimide,hexadecyltrimethylammonium halide, tetradecyltrimethylammonium halide,dodecyltrimethylammonium halide, cetrimonium halide, benzethoniumhalide, behenalkonium halide, cetalkonium halide, cetethykdimoniumhalide, cetylpyridinium halide, benzododecinium halide, chlorallylmethenamine halide, myristylalkonium halide, stearalkonium halide or amixture of two or more thereof. In some cases, cationic agent can be abenzalkonium chloride, lauralkonium chloride, benzododecinium bromide,benzethenium chloride, hexadecyltrimethylammonium bromide,tetradecyltrimethylammonium bromide, dodecyltrimethylammonium bromide ora mixture of two or more thereof. In some cases, the oil phase can bemineral oil and light mineral oil, medium chain triglycerides (MCT),coconut oil; hydrogenated oils comprising hydrogenated cottonseed oil,hydrogenated palm oil, hydrogenate castor oil or hydrogenated soybeanoil; polyoxyethylene hydrogenated castor oil derivatives comprisingpoluoxyl-40 hydrogenated castor oil, polyoxyl-60 hydrogenated castor oilor polyoxyl-100 hydrogenated castor oil.

In some embodiments, the amount of a compound as disclosed herein in theformulation can be about 0.5% to about 20%, 0.5% to about 10%, or about1.5% w/w.

1F. Formulations for Controlled Release Administration

In some embodiments, provided herein are pharmaceutical compositions forcontrolled release administration containing a compound as disclosedherein, and one or more pharmaceutical excipients suitable forcontrolled release administration. In some embodiments, provided hereinare pharmaceutical compositions for controlled release administrationcontaining: (i) an effective amount of a disclosed compound; optionally(ii) an effective amount of one or more second agents; and (iii) one ormore pharmaceutical excipients suitable for controlled releaseadministration. In some embodiments, the pharmaceutical compositionfurther contains: (iv) an effective amount of a third agent.

Active agents such as the compounds provided herein can be administeredby controlled release means or by delivery devices that are well knownto those of ordinary skill in the art. Examples include, but are notlimited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899;3,536,809; 3,598,123; and 4,008,719; 5,674,533; 5,059,595; 5,591,767;5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566;5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855;6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970;6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,699,500 each ofwhich is incorporated herein by reference. Such dosage forms can be usedto provide slow or controlled release of one or more active agentsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active agents provided herein. Thus, the pharmaceuticalcompositions provided encompass single unit dosage forms suitable fororal administration such as, but not limited to, tablets, capsules,gelcaps, and caplets that are adapted for controlled release.

All controlled release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non controlledcounterparts. In some embodiments, the use of a controlled releasepreparation in medical treatment can be characterized by a minimum ofdrug substance being employed to cure or control the disease, disorder,or condition in a minimum amount of time. Advantages of controlledrelease formulations include extended activity of the drug, reduceddosage frequency, and increased subject compliance. In addition,controlled release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

In some embodiments, controlled release formulations are designed toinitially release an amount of a compound as disclosed herein thatpromptly produces the desired therapeutic effect, and gradually andcontinually release other amounts of the compound to maintain this levelof therapeutic or prophylactic effect over an extended period of time.In order to maintain this constant level of the compound in the body,the compound should be released from the dosage form at a rate that willreplace the amount of drug being metabolized and excreted from the body.Controlled release of an active agent can be stimulated by variousconditions including, but not limited to, pH, temperature, enzymes,water, or other physiological conditions or compounds.

In certain embodiments, the pharmaceutical composition can beadministered using intravenous infusion, an implantable osmotic pump, atransdermal patch, liposomes, or other modes of administration. In oneembodiment, a pump can be used (see, Sefton, CRC Crit. Ref Biomed. Eng.14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Sandek et al., N.Engl. J. Med. 321:574 (1989)). In another embodiment, polymericmaterials can be used. In yet another embodiment, a controlled releasesystem can be placed in a subject at an appropriate site determined by apractitioner of skill, i.e., thus requiring only a fraction of thesystemic dose (see, e.g., Goodson, Medical Applications of ControlledRelease, 115-138 (vol. 2, 1984). Other controlled release systems arediscussed in the review by Langer, Science 249:1527-1533 (1990). The oneor more active agents can be dispersed in a solid inner matrix, e.g.,polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydxogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydxolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The one or more active agents then diffuse through the outer polymericmembrane in a release rate controlling step. The percentage of activeagent in such parenteral compositions can depend on the specific naturethereof, as well as the needs of the subject.

2. Dosage

A compound described herein can be delivered in the form ofpharmaceutically acceptable compositions which comprise atherapeutically effective amount of one or more compounds describedherein and/or one or more additional therapeutic agents such as achemotherapeutic, formulated together with one or more pharmaceuticallyacceptable excipients. In some embodiments, only a compound providedherein without an additional therapeutic agent can be included in thedosage form. In some instances, the compound described herein and theadditional therapeutic agent are administered in separate pharmaceuticalcompositions and can (e.g., because of different physical and/orchemical characteristics) be administered by different routes (e.g., onetherapeutic can be administered orally, while the other can beadministered intravenously). In other instances, the compound describedherein and the additional therapeutic agent can be administeredseparately, but via the same route (e.g., both orally or bothintravenously). In still other instances, the compound described hereinand the additional therapeutic agent can be administered in the samepharmaceutical composition.

The selected dosage level will depend upon a variety of factorsincluding, for example, the activity of the particular compoundemployed, the severity of the condition, the route of administration,the time of administration, the rate of excretion or metabolism of theparticular compound being employed, the rate and extent of absorption,the duration of the treatment, administration of other drugs, compoundsand/or materials used in combination with the particular compoundemployed, the age, sex, weight, condition, general health and priormedical history of the patient being treated, and like factors wellknown in the medical arts.

The dosage level can also be informed by in vitro or in vivo assayswhich can optionally be employed to help identify optimal dosage ranges.A rough guide to effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems.

In general, a suitable daily dose of a compound described herein and/ora chemotherapeutic will be that amount of the compound which, in someembodiments, can be the lowest dose effective to produce a therapeuticeffect. Such an effective dose will generally depend upon the factorsdescribed above. Generally, doses of the compounds described herein fora patient, when used for the indicated effects, will range from about0.0001 mg to about 100 mg per day, or about 0.001 mg to about 100 mg perday, or about 0.01 mg to about 100 mg per day, or about 0.1 mg to about100 mg per day, or about 0.1 mg to about 125 mg per day, or about 0.0001mg to about 500 mg per day, or about 0.001 mg to about 500 mg per day,or about 0.01 mg to about 1000 mg per day, or about 0.01 mg to about 500mg per day, or about 0.1 mg to about 500 mg per day, or about 1 mg toabout 25 mg per day, or about 1 mg to about 50 mg per day, or about 5 mgto about 40 mg per day. An exemplary dosage can be about 10 to about 30mg per day. In some embodiments, for a 70 kg human, a suitable dosewould be about 0.05 to about 7 g/day, such as about 0.05 to about 2g/day. Actual dosage levels of the active ingredients in thepharmaceutical compositions described herein can be varied so as toobtain an amount of the active ingredient which is effective to achievethe desired therapeutic response for a particular patient, composition,and mode of administration, without being toxic to the patient. In someinstances, dosage levels below the lower limit of the aforesaid rangecan be more than adequate, while in other cases still larger doses canbe employed without causing any harmful side effect, e.g., by dividingsuch larger doses into several small doses for administration throughoutthe day.

In some embodiments, the compounds can be administered daily, everyother day, three times a week, twice a week, weekly, bi-weekly, oranother intermittent schedule. The dosing schedule can include a “drugholiday,” i.e., the drug can be administered for two weeks on, one weekoff, or three weeks on, one week on, or four weeks on, one week off,etc., or continuously, without a drug holiday. The compounds can beadministered orally, rectally, parenterally, intravenously,intraperitoneally, topically, transdermally, intramuscularly,subcutaneously, intracistemally, intravaginally, intranasally,sublingually, bucally, or by any other route.

In some embodiments, a compound as provided herein can be administeredin multiple doses. Dosing can be about once, twice, three times, fourtimes, five times, six times, or more than six times per day. Dosing canbe about once a month, about once every two weeks, about once a week, orabout once every other day. In another embodiment, a compound asdisclosed herein and another agent are administered together about onceper day to about 6 times per day. For example, the compound can beadministered one or more times per day on a weekly basis (e.g., everyMonday) indefinitely or for a period of weeks, e.g., 4-10 weeks.Alternatively, it can be administered daily for a period of days (e.g.,2-10 days) followed by a period of days (e.g., 1-30 days) withoutadministration of the compound, with that cycle repeated indefinitely orfor a given number of repetitions, e.g., 4-10 cycles. As an example, acompound provided herein can be administered daily for 5 days, thendiscontinued for 9 days, then administered daily for another 5 dayperiod, then discontinued for 9 days, and soon, repeating the cycleindefinitely, or for a total of 4-10 times. In another embodiment, theadministration of a compound as provided herein and an agent continuesfor less than about 7 days. In yet another embodiment, theadministration continues for more than about 6, about 10, about 14,about 28 days, about two months, about six months, or about one year. Insome cases, continuous dosing can be achieved and maintained as long asnecessary.

Administration of the pharmaceutical compositions as disclosed hereincan continue as long as necessary. In some embodiments, an agent asdisclosed herein can be administered for more than about 1, about 2,about 3, about 4, about 5, about 6, about 7, about 14, or about 28 days.In some embodiments, an agent as disclosed herein can be administeredfor less than about 28, about 14, about 7, about 6, about 5, about 4,about 3, about 2, or about 1 day. In some embodiments, an agent asdisclosed herein can be administered chronically on an ongoing basis,e.g., for the treatment of chronic effects.

Since the compounds described herein can be administered in combinationwith other treatments (such as additional chemotherapeutics, radiationor surgery), the doses of each agent or therapy can be lower than thecorresponding dose for single-agent therapy. The dose for single agenttherapy can range from, for example, about 0.0001 to about 200 mg, orabout 0.001 to about 100 mg, or about 0.01 to about 100 mg, or about 0.1to about 100 mg, or about 1 to about 50 mg per kilogram of body weightper day.

When a compound provided herein is administered in a pharmaceuticalcomposition that comprises one or more agents, and one or more of theagents has a shorter half-life than the compound provided herein, unitdose forms of the agent(s) and the compound provided herein can beadjusted accordingly.

3. Kits

In some embodiments, provided herein are kits. The kits can include acompound or pharmaceutical composition as described herein, in suitablepackaging, and written material that can include instructions for use,discussion of clinical studies, listing of side effects, and the like.Kits are well suited for the delivery of solid oral dosage forms such astablets or capsules. Such kits can also include information, such asscientific literature references, package insert materials, clinicaltrial results, and/or summaries of these and the like, which indicate orestablish the activities and/or advantages of the pharmaceuticalcomposition, and/or which describe dosing, administration, side effects,drug interactions, or other information useful to the health careprovider. Such information can be based on the results of variousstudies, for example, studies using experimental animals involving invivo models and studies based on human clinical trials.

In some embodiments, a memory aid can be provided with the kit, e.g., inthe form of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid canbe a calendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc . . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several tablets or capsules to betaken on a given day.

The kit can further contain another agent. In some embodiments, thecompound as disclosed herein and the agent are provided as separatepharmaceutical compositions in separate containers within the kit. Insome embodiments, the compound as disclosed herein and the agent areprovided as a single pharmaceutical composition within a container inthe kit. Suitable packaging and additional articles for use (e.g.,measuring cup for liquid preparations, foil wrapping to minimizeexposure to air, and the like) are known in the art and can be includedin the kit. In other embodiments, kits can further comprise devices thatare used to administer the active agents. Examples of such devicesinclude, but are not limited to, syringes, drip bags, patches, andinhalers. Kits described herein can be provided, marketed and/orpromoted to health providers, including physicians, nurses, pharmacists,formulary officials, and the like. Kits can also, in some embodiments,be marketed directly to the consumer.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process, recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. The strength of the sheet is such that the tablets or capsulescan be removed from the blister pack by manually applying pressure onthe recesses whereby an opening is formed in the sheet at the place ofthe recess. The tablet or capsule can then be removed via said opening.

Kits can further comprise pharmaceutically acceptable vehicles that canbe used to administer one or more active agents. For example, if anactive agent is provided in a solid form that must be reconstituted forparenteral administration, the kit can comprise a sealed container of asuitable vehicle in which the active agent can be dissolved to form aparticulate free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

The present disclosure further encompasses anhydrous pharmaceuticalcompositions and dosage forms comprising an active ingredient, sincewater can facilitate the degradation of some compounds. For example,water can be added (e.g., about 5%) in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. Anhydrous pharmaceutical compositions and dosage forms can beprepared using anhydrous or low moisture containing ingredients and lowmoisture or low humidity conditions. For example, pharmaceuticalcompositions and dosage forms which contain lactose can be madeanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected. An anhydrouspharmaceutical composition can be prepared and stored such that itsanhydrous nature is maintained. Accordingly, anhydrous pharmaceuticalcompositions can be packaged using materials known to prevent exposureto water such that they can be included in suitable formulary kits.Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastic or the like, unit dose containers,blister packs, and strip packs.

Therapeutic Methods

As used herein, a “mutant EGFR-mediated disorder” refers to a disease orcondition involving an aberrant EGFR-mediated signaling pathwayassociated with the EGFR having one or more mutations in any of itsexons and includes having one or more mutations in the exon 20 domain.In one embodiment, the mutant EGFR has one or more mutations in the exon20 domain. In another embodiment, the mutant EGFR-mediated disorder canbe associated with EGFR having one or more mutations in the exon 20domain.

As used herein, a “mutant HER2-mediated disorder” refers to a disease orcondition involving an aberrant HER2-mediated signaling pathwayassociated with the EGFR having one or more mutations in any of itsexons and includes having one or more mutations in the exon 20 domain.In one embodiment, the mutant HER2 has one or more mutations in the exon20 domain. In another embodiment, the mutant HER2-mediated disorder canbe associated with HER2 having one or more mutations in the exon 20domain.

In some embodiments, a method is provided for inhibiting mutant EGFRactivity by contacting the mutant EGFR with an effective amount of acompound, or a pharmaceutically acceptable form (e.g., pharmaceuticallyacceptable salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives) thereof, or a pharmaceuticalcomposition as provided herein, in some cases in solution, to inhibitthe mutant EGFR kinase activity. In some embodiments, methods areprovided for inhibiting the mutant EGFR activity by contacting a cell,tissue, or organ that expresses the mutant EGFR with a compound providedherein. In some embodiments, methods are provided for inhibiting themutant EGFR activity in a subject (including mammals such as humans) byadministering into the subject an effective amount of a compound asprovided herein to inhibit or reduce the activity of the mutant EGFR inthe subject. In some embodiments, the kinase activity can be inhibited(e.g., reduced) by more than about 25%, about 30%, about 40%, about 50%,about 60%, about 70%, about 80%, or about 90% when contacted with acompound provided herein as compared to the kinase activity without suchcontact. In some embodiments, the kinase can be exon 20 mutant EGFR. Forinstance, the mutant EGFR can be exon 20 mutant EGFR.

In EGFR kinase, the exon 20 domain lies in a loop beginning at theC-terminal side of the kinase's C-helix. (Yasuda 2012) Exon 20 in HER2is in a similar position. While the C-helix forms a portion of theactive site, the exon 20 loop exerts a more indirect conformationalmotion when mutated. The conformational change affects the C-helix suchthat the active site pocket is altered in a subtle manner. Without beingbound by any one theory, this conformational change can enable selectiveinhibition of exon 20 mutant EGFR and/or exon 20 mutant HER2 relative towild-type EGFR.

In some embodiments, the exon 20 mutant EGFR has insertion mutations inits exon 20 domain. Insertion mutations have been documented for atleast residues 762-774 of EGFR, with those involving amino acids A767,S768, V769, D770, P772 and H773 displaying a lack of response whentreated with known inhibitors, such as gefitinib or erlotinib. (Yasuda2012). Other types of mutations can occur in the exon 20 domain, such asthe T790M “gatekeeper” point mutation, which lies in the active site ofEGFR. T790M mutations can occur in conjunction with deletion mutationssuch as DT and other point mutations such as LT. Disclosed compounds canhave inhibitory activity against T790M mutated EGFR and activity againstexon 20 insertion mutants.

In one embodiment, the disclosed compounds show inhibitory activitytowards one or more of the EGFR exon 20 insertion mutants shown inTable 1. The relative frequency is derived from a survey of publishedclinical trials in which the EGFR mutation(s) in the patient weredetermined. (Yasuda 2012).

TABLE 1 Relative EGFR amino acid Insertion Mutation Frequency 767Ala767_Ser768insThrLeuAla 2.5% 768 Ser768_Val769insValAlaSer 5.7%Ser768_Val769insAlaTrpThr 769 Val769_Asp770insAlaSerVal 20.5% Val769_Asp770insGlyVal Val769_Asp770insCysVal Val769_Asp770insAspAsnValVal769_Asp770insGlySerVal Val769_Asp770insGlyValValVal769_Asp770insMetAlaSerValAsp (SEQ ID NO: 1) 770Asp770_Asn771insSerValAsp 28.7%  Asp770_Asn771insAsnProGlyAsp770_Asn771insAlaProTrp Asp770_Asn771insAsp Asp770_Asn771insAspGlyAsp770_Asn771insGly Asp770_Asn771insGlyLeu Asp770_Asn771insAsnAsp770_Asn771insAsnProHis Asp770_Asn771insSerValProAsp770_Asn771insSerValGln Asp770_Asn771insMetAlaThrPro (SEQ ID NO: 2)delAsp770insGlyTyr 771 Asn771_Pro772insHis 4.1% Asn771_Pro772insAsndelAsn771insGlyTyr delAsn771insGlyPhe 772 Pro772_His773insProArg 17.2% Pro772_His773insTyrAsnPro Pro772_His773insX Pro772_His773insAspProHisPro772_His773insAspAsnPro Pro772_His773insGlnValPro772_His773insThrProHis Pro772_His773insAsn Pro772_His773insVal 773His773_Val774insAsnProHis  14% His773_Val774insHisHis773_Val774insProHis His773_Val774insGlyAsnProHis (SEQ ID NO: 3)His773_Val774insGly His773_Val774insGlyHis 774 Val774_Cys775insHisVal3.3%

In another embodiment, the compounds disclosed herein show inhibitoryactivity towards the exon 20 mutant EGFR Val769_Asp770insAlaSerValand/or the Asp770_Asn771insAsnProGly insertion mutations. In someembodiments, the compounds disclosed herein show inhibitory activitytowards one or more of the exon 20 mutant EGFR Asp770_Asn771insSVD, theHis773_Val774insNPH, and the Ala763_Tyr764insFQEA (SEQ ID NO: 4)insertion mutations. Provided herein, methods of treatment for a mutantEGFR-mediated disorder include subjects who have an exon 20 insertionmutation as listed in Table 1. In other embodiments, the exon 20insertion mutation can be selected from Val769_Asp770insAlaSerVal and/orthe Asp770_Asn771 insAsnProGly. In other embodiments, the exon 20insertion mutation can be selected from Asp770_Asn771insSVD,His773_Val774insNPH, and Ala763_Tyr764insFQEA (SEQ ID NO: 4).

In some embodiments, methods are disclosed for inhibiting mutant HER2activity (e.g., selectively modulating) by contacting the HER2 with aneffective amount of a compound, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, or apharmaceutical composition as provided herein, to inhibit the HER2activity. In some embodiments, the mutant HER2 has one or more exon 20mutations. In some embodiments, methods are provided for inhibitingkinase activity by contacting the kinase with a solution containing aneffective amount of the compound to inhibit the HER2. In someembodiments, methods are provided for inhibiting the HER2 kinaseactivity by contacting a cell, tissue, or organ that express the kinasewith a compound provided herein. In some embodiments, methods ofinhibiting kinase activity in a subject by administering into thesubject an effective amount of a compound as provided herein. In someembodiments, the kinase activity can be inhibited (e.g., reduced) bymore than about 25%, about 30%, about 40%, about 50%, about 60%, about70%, about 80%, or about 90% when contacted with a compound providedherein as compared to the kinase activity without such contact. In someembodiments, the kinase can be exon 20 mutant HER2. In some embodiments,provided herein are methods of inhibiting mutant HER2 activity in asubject (including mammals such as humans) by contacting said subjectwith an amount of a compound as provided herein sufficient to inhibit orreduce the activity of the mutant HER2 in said subject. For instance,the mutant HER2 can be exon 20 mutant HER2.

In some embodiments, the exon 20 mutant HER2 has insertion mutations inits exon 20 domain that have been documented for at least residues770-831 of HER2. (Arcila 2012; Shigematsu et. al. Cancer Res 2005;65:1642-46). In one embodiment, the disclosed compounds show inhibitoryactivity towards one or more of the HER2 exon 20 insertion mutants shownin Table 2.

TABLE 2 Relative HER2 amino acid Point and Insertion Mutations Frequency775 Ala775_Gly776insTyrValMetAla 80%  (SEQ ID NO: 5) 776 Gly776 > ValCys8% 780 Pro780_Tyr781insGlySerPro 4% 776 and 777 Gly776Cys and 4%Val777_Gly778insCysGly

In another embodiment, the compounds disclosed herein show inhibitoryactivity towards the A1a775_Gly776insTyrValMetAla (SEQ ID NO: 5) exon 20mutant HER2 insertion mutations. The disclosed methods of treatment fora mutant HER2-mediated disorder are applicable to those subjects, amongothers, who have exon 20 insertion mutation Ala775_Gly776insTyrValMetAla(SEQ ID NO: 5) or another exon 20 insertion mutation listed in Table 2.

In some embodiments, the compounds disclosed herein show inhibitoryactivity against the wild type receptor tyrosine kinases that includeEGFR/ERBB1, HER2/ERBB2/NEU, HER3/ERBB3, and HER4/ERBB4.

In one embodiment, provided herein is a method of treating a mutantEGFR-mediated disorder in a subject, the method comprising administeringa therapeutically effective amount of a compound or a pharmaceuticalcomposition as provided herein. In some embodiments, provided herein isa method of ameliorating a mutant EGFR-mediated disorder in a subject,the method comprising administering a therapeutically effective amountof a compound or a pharmaceutical composition as provided herein. Insome embodiments, provided herein is a method for inhibiting mutantEGFR, the method comprising contacting a cell expressing mutant EGFR invitro or in vivo with an effective amount of the compound or compositionprovided herein. In all these embodiments, the mutant can be, forexample, an exon 20 insertion mutant. In another aspect, in all theabove embodiments the mutant can be an exon 20 point mutation,optionally accompanied by another mutation such as D or L.

In some embodiments, provided herein are methods of treating a mutantEGFR-mediated disorder, such as where the mutation is an exon 20insertion, that is resistant to another anti-cancer agent(s) (e.g.,erlotinib, gefitinib, neratinib, afatinib, dacomitinib), the methodinvolving administering a therapeutic effective amount of a compound ofFormula I to a subject in need thereof.

Without being limited by a particular theory, EGFR having one or moreexon 20 insertion mutations has been associated with lung cancer (e.g.,non-small cell lung cancer NSCLC, lung adenocarcinoma), colorectalcancer, pancreatic cancer, and head and neck cancers. Exon 20 insertionmutations are most prevalent in NSCLC: 15% of western Europeans, 30%East Asians, and 50% of non-smokers. (Yasuda 2012). In head and neckcancers, current therapies targeting mutant EGFR include cetuximab, achimeric mouse-human IgG1antibody. (Chong et al. 2013). Exon 20 mutantEGFR colorectal cancer has been treated using cetuximab and panitumumab,a fully humanized IgG2 antibody. Id. Exon 20 mutant EGFR pancreaticcancer has been treated with erlotinib. Id. EGFR having the T790M pointmutation, optionally accompanied by exon 19 D and/or exon 21 Lmutations, have been associated with NSCLC where the cancer hasdeveloped resistance to one or more other TKI's such as erlotinib andgefitinib.

Without being limited by a particular theory, HER2 having one or moreexon 20 insertion mutations has been associated with lung cancer (e.g.,NSCLC), breast cancer, ovarian cancer, uterine cancer, and stomachcancer. (Santin et al. Int J Gynaecol Obstet 2008; 102:128-31). Currenttherapies include Herceptin and pertuzamab. HER2 mutations are presentin about 2-4% of NSCLC: 80-84% of those patients have the YVMA exon 20insertion mutation. (Arcila 2012).

In some embodiments, provided herein are methods of using a compound ofFormula I, or a pharmaceutically acceptable form (e.g., pharmaceuticallyacceptable salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives) thereof, or pharmaceuticalcompositions as provided herein to treat disease conditions, including,but not limited to, diseases associated with one or more types of mutantEGFR or mutant HER2. In some embodiments, the disclosure relates to amethod of treating a hyperproliferative disorder in a subject thatcomprises administering to said subject a therapeutically effectiveamount of a compound, or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, or apharmaceutical composition as provided herein.

Compounds and pharmaceutical compositions are disclosed herein for themanufacture of a medicament for treating a mutant EGFR or mutant HER2disorder in a subject in need thereof. Also provided are compounds andpharmaceutical compositions for the treatment of a mutant EGFR-mediateddisorder or mutant HER2-mediated disorder in a subject in need thereof.In all of the above embodiments, the mutant can be an exon 20 insertionmutation. In another aspect, in all the above embodiments the mutant canbe an exon 20 point mutation, optionally accompanied by another mutationsuch as D or L.

Patients that can be treated with compounds, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or pharmaceutical compositions as provided herein, according tothe methods as provided herein include, but are not limited to, patientsthat have been diagnosed as having lung cancer, colorectal cancer,pancreatic cancer and head and neck cancers. In other embodiments, apatient can be diagnosed with lung cancer, breast cancer, ovariancancer, uterine cancer, and stomach cancer. Efficacy of a compoundprovided herein in treating, preventing and/or managing the disease ordisorder can be tested using various animal models known in the art.See, e.g., Yasuda 2012.

In some embodiments, a symptom associated with a disease or disorderprovided herein can be reduced by at least about 10%, at least about20%, at least about 30%, at least about 40%, at least about 50%, atleast about 60%, at least about 70%, at least about 80%, at least about90%, or at least about 95% relative to a control level. The controllevel includes any appropriate control as known in the art. For example,the control level can be the pre-treatment level in the sample orsubject treated, or it can be the level in a control population (e.g.,the level in subjects who do not have the disease or disorder or thelevel in samples derived from subjects who do not have the disease ordisorder). In some embodiments, the decrease can be statisticallysignificant, for example, as assessed using an appropriate parametric ornon-parametric statistical comparison.

In some embodiments, treatment of a mutant EGFR-mediated disorder or amutant HER2-mediated disorder involves administering (as a monotherapyor in combination with one or more other anti-cancer agents, one or moreagents for ameliorating side effects, radiation, etc) a therapeuticallyeffective amount of a compound disclosed herein to a human or animal inneed of it in order to inhibit, slow or reverse the growth, developmentor spread of cancer, including solid tumors or other forms of cancersuch as leukemias, in the subject. Such administration constitutes amethod for the treatment or prophylaxis of diseases mediated by one ormore kinases inhibited by one of the disclosed compounds or apharmaceutically acceptable form thereof. In one embodiment, the mutantcan be an exon 20 insertion mutation.

Combination Therapy

In some embodiments, provided herein are methods for combinationtherapies in which an agent known to modulate other pathways, or othercomponents of the same pathway, or even overlapping sets of targetenzymes are used in combination with a compound as provided herein, or apharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof. In one aspect, such therapy includes, but is notlimited to, the combination of the subject compound withchemotherapeutic agents, therapeutic antibodies, and radiationtreatment, to provide a synergistic or additive therapeutic effect.

When administered as a combination, the therapeutic agents can beformulated as separate compositions that are administered at the sametime or sequentially at different times, or the therapeutic agents canbe given as a single composition. The phrase “combination therapy”, inreferring to the use of a disclosed compound together with anotherpharmaceutical agent, means the coadministration of each agent in asubstantially simultaneous manner as well as the administration of eachagent in a sequential manner, in either case, in a regimen that willprovide beneficial effects of the drug combination. Coadministrationincludes, inter alia, the simultaneous delivery, e.g., in a singletablet, capsule, injection or other dosage form having a fixed ratio ofthese active agents, as well as the simultaneous delivery in multiple,separate dosage forms for each agent respectively. Thus, theadministration of disclosed compounds can be in conjunction withadditional therapies known to those skilled in the art in the preventionor treatment of cancer, such as radiation therapy or cytostatic agents,cytotoxic agents, other anti-cancer agents and other drugs toamerliorate symptoms of the cancer or side effects of any of the drugs.

If formulated as a fixed dose, such combination products employ thedisclosed compounds within suitable dosage ranges. Compounds providedherein can also be administered sequentially with other anticancer orcytotoxic agents when a combination formulation is inappropriate. Asdefined herein, combination therapy is not limited in the sequence ofadministration; disclosed compounds can be administered prior to,simultaneously with, or after administration of the other anticancer orcytotoxic agent.

In some embodiments, pharmaceutical compositions disclosed herein caninclude a compound as described herein or a pharmaceutically acceptablesalt thereof; an additional agent selected from a kinase inhibitoryagent (small molecule, polypeptide, antibody, etc.), animmunosuppressant, an anticancer agent, an anti-viral agent,antiinflammatory agent, antifungal agent, antibiotic, or ananti-vascular hyperproliferation compound; and any pharmaceuticallyacceptable carrier, adjuvant or vehicle.

Alternate pharmaceutical compositions disclosed herein include acompound as described herein or a pharmaceutically acceptable saltthereof; and a pharmaceutically acceptable carrier, adjuvant or vehicle.Such compositions can optionally comprise one or more additionaltherapeutic agents, including, for example, kinase inhibitory agents(small molecule, polypeptide, antibody, etc.), immunosuppressants,anti-cancer agents, anti-viral agents, antiinflammatory agents,antifungal agents, antibiotics, or anti-vascular hyperproliferationcompounds.

In one aspect, a compound as provided herein, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or pharmaceutical compositions as provided herein, can presentsynergistic or additive efficacy when administered in combination withagents that inhibit other kinase(s) production or activity. Suchcombination can reduce undesired side effect of the compounds andcompositions described herein, if such effect occurs.

In some embodiments, treatment can be provided in combination with oneor more other cancer therapies, include surgery, radiotherapy (e.g.,gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy,proton therapy, brachytherapy, and systemic radioactive isotopes, etc.),endocrine therapy, biologic response modifiers (e.g., interferons,interleukins, and tumor necrosis factor (TNF)), hyperthermia,cryotherapy, agents to attenuate any adverse effects (e.g.,antiemetics), and other cancer chemotherapeutic drugs. The otheragent(s) can be administered using a formulation, route ofadministration and dosing schedule the same or different from that usedwith the compounds provided herein.

For treatment of mutant EGFR-mediated diseases and mutant HER2-mediateddiseases, a compound as provided herein, or a pharmaceuticallyacceptable form (e.g., pharmaceutically acceptable salts, hydrates,solvates, isomers, prodrugs, and isotopically labeled derivatives)thereof, or pharmaceutical compositions as provided herein, can be usedin combination with commonly prescribed drugs including, but not limitedto, anti-cancer drugs (e.g., antiproliferative agents, anti-angiogenicagents and other chemotherapeutic agents). In another aspect, providedherein is a pharmaceutical composition for inhibiting abnormal cellgrowth in a subject which comprises an amount of a compound as providedherein, or a pharmaceutically acceptable form (e.g., pharmaceuticallyacceptable salts, hydrates, solvates, isomers, prodrugs, andisotopically labeled derivatives) thereof, in combination with an amountof an anti-cancer agent (e.g., a chemotherapeutic agent). Manychemotherapeutics are presently known in the art and can be used incombination with the compounds as provided herein. In some embodiments,the chemotherapeutic can be selected from mitotic inhibitors, alkylatingagents, anti-metabolites, intercalating antibiotics, growth factorinhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors,biological response modifiers, anti-hormones, angiogenesis inhibitors,antibiotics, immunological agents, interferon-type agents, andanti-androgens. Non-limiting examples include chemotherapeutic agents,cytotoxic agents, and non-peptide small molecules such as Gleevec®(Imatinib Mesylate), Velcade® (bortezomib), Casodex (bicalutamide),Iressa®, and Adriamycin as well as a host of chemotherapeutic agents.Non-limiting examples of chemotherapeutic agents include alkylatingagents such as thiotepa and cyclosphosphamide (CYTOXAN®); alkylsulfonates such as busulfan, improsulfan and piposulfan; aziridines suchas benzodopa, carboquone, meturedopa, and uredopa; ethylenimines andmethylamelamines including altretamine, triethylenemelamine,trietylenephosphoramide, triethylenethiophosphaoramide andtrimethylolomelamine; BTK inhibitors such as ibrutinib (PCI-32765) andAVL-292; HDAC inhibitors such as vorinostat, romidepsin, panobinostat,valproic acid, belinostat, mocetinostat, abrexinostat, entinostat,SB939, resminostat, givinostat, CUDC-101, AR-42, CHR-2845, CHR-3996,4SC-202, CG200745, ACY-1215 and kevetrin; JAK-STAT inhibitors such aslestaurtinib, tofacitinib, ruxolitinib, pacritinib, CYT387, baricitinib,fostamatinib, GLPG0636, TG101348, INCB16562 and AZD1480; nitrogenmustards such as bedamustine, chlorambucil, chlornaphazine,cholophosphamide, estramustine, ifosfamide, mechlorethamine,mechlorethamine oxide hydrochloride, melphalan, novembichin,phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureassuch as carmustine, chlorozotocin, fotemustine, lomustine, nimustine,ranimustine; antibiotics such as acacinomysins, actinomycin,authramycin, azaserine, bleomycins, cactinomycin, calicheamicin,carabicin, caminomycin, carzinophilin, Casodexm, chromomycins,dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine,doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin,mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin,potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin,streptozocin, tubercidin, ubenimex, zinostatin, zorubicin;anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folicacid analogues such as denopterin, methotrexate, pralatrexate,pteropterin, trimetrexate; purine analogs such as fludarabine,6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such asancitabine, azacitidine, 6-azauridine, carmofur, cytarabine,dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens suchas calusterone, dromostanolone propionate, epitiostanol, mepitiostane,testolactone; anti-adrenals such as aminoglutetimide, mitotane,trilostane; folic acid replenisher such as frolinic acid; aceglatone;aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil;bisantrene; edatraxate; defofamine; demecolcine; diaziquone;elformithine; elliptinium acetate; etoglucid; gallium nitrate;hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol;nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid;2-ethylhydrazide; procarbazine; PSK®; razoxane; sizofuran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethyla-mine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g.,paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, N.J.) anddocetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France) and ABRAXANE®(paclitaxel protein-bound particles); retinoic acid; esperamicins;capecitabine; and pharmaceutically acceptable forms (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) of any of the above.Also included as suitable chemotherapeutic cell conditioners areanti-hormonal agents that act to regulate or inhibit hormone action ontumors such as anti-estrogens including, for example, tamoxifen(Nolvadex™), raloxifene, aromatase inhibiting 4(5)-imidazoles,4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, andtoremifene (Fareston); and anti-androgens such as flutamide, nilutamide,bicalutamide, leuprolide, and goserelin; chlorambucil; gemcitabine;6-thioguanine; mercaptopurine; methotrexate; platinum analogs such ascisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16);ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine;navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda;ibandlonate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS 2000;and difluoromethylomithine (DMFO).

Where desired, the compounds or pharmaceutical compositions as providedherein can be used in combination with commonly prescribed anti-cancerdrugs such as, but not limited to, Herceptin®, Avastin®, Erbitux®,Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab,Acridine carboxamide, Adecatumumab,17-N-Allylamino-17-demethoxygeldanamycin, Alpharadin, Alvocidib,3-Aminopyridine-2-carboxaldehyde thiosemicarbazone, Amonafide,Anthracenedione, Anti-CD22 immunotoxins, Antineoplastic, Antitumorigenicherbs, Apaziquone, Atiprimod, Azathioprine, Belotecan, Bendamustine,BIBW 2992, Biricodar, Brostallicin, Bryostatin, Buthionine sulfoximine,CBV (chemotherapy), Calyculin, Crizotinib, cell-cycle nonspecificantineoplastic agents, Dichloroacetic acid, Discodermolide,Elsamitrucin, Enocitabine, Epothilone, Eribulin, Everolimus, Exatecan,Exisulind, Ferruginol, Forodesine, Fosfestrol, ICE chemotherapy regimen,IT-101, Imexon, Imiquimod, Indolocarbazole, Irofulven, Laniquidar,Larotaxel, Lenalidomide, Lucanthone, Lurtotecan, Mafosfamide,Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel, PAC-1,Pawpaw, Pixantrone, Proteasome inhibitor, Rebeccamycin, Resiquimod,Rubitecan, SN-38, Salinosporamide A, Sapacitabine, Stanford V,Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar, Tesetaxel,Triplatin tetranitrate, Tris(2-chloroethyl)amine, Troxacitabine,Uramustine, Vadimezan, Vinflunine, ZD6126, and Zosuquidar.

Other chemotherapeutic agents include, but are not limited to,anti-estrogens (e.g. tamoxifen, raloxifene, and megestrol), LHRHagonists (e.g. goscrclin and leuprolide), anti-androgens (e.g. flutamideand bicalutamide), photodynamic therapies (e.g. vertoporfin (BPD-MA),phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A(2BA-2-DMHA)), nitrogen mustards (e.g. cyclophosphamide, ifosfamide,trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas(e.g. carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g.busulfan and treosuifan), triazenes (e.g. dacarbazine, temozolomide),platinum containing compounds (e.g. cisplatin, carboplatin,oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine,and vinorelbine), taxoids (e.g. paditaxel or a paclitaxel equivalentsuch as nanopartide albumin-bound paclitaxel (Abraxane), docosahexaenoicacid bound-paditaxel (DHA-paditaxel, Taxoprexin), polyglutamatebound-paclitaxel (PG-paclitaxel, paditaxel poliglumex, CT-2103, XYOTAX),the tumor-activated prodrug (TAP), ANG1005 (Angiopep-2 bound to threemolecules of paclitaxel), paclitaxel-EC-1 (paditaxel bound to theerbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel,e.g., 2′-paditaxel methyl 2-glucopyranosyl succinate; docetaxel, taxol),epipodophyllins (e.g. etoposide, etoposide phosphate, teniposide,topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol,mytomycin C), anti-metabolites, DHFR inhibitors (e.g. methotrexate,dichloromethotrexate, timetrexate, edatrexate), IMP dehydrogenaseinhibitors (e.g. mycophenolic acid, tiazofurin, ribavirin, and EICAR),ribonudeotide reductase inhibitors (e.g. hydroxyurea and deferoxamine),uracil analogs (e.g. 5-fluorouracil (5-FU), floxuridine, doxifluridine,ratitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g.cytarabine (ara C), cytosine arabinoside, and fludarabine), purineanalogs (e.g. mercaptopurine and Thioguanine), Vitamin D3 analogs (e.g.EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g.lovastatin), dopaminergic neurotoxins (e.g. 1-methyl-4-phenylpyridiniumion), cell cycle inhibitors (e.g. staurosporine), actinomycin (e.g.actinomycin D, dactinomycin), bleomycin (e.g. bleomycin A2, bleomycinB2, peplomycin), anthracycline (e.g. daunorubicin, doxorubicin,pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin,zorubicin, mitoxantrone), MDR inhibitors (e.g. verapamil), Ca²⁺ ATPaseinhibitors (e.g. thapsigargin), imatinib, thalidomide, lenalidomide,tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib(SKI-606), cediranib (RECENTIN™, AZD2171), dasatinib (SPRYCEL®,BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib(Gleevece, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®),lestaurtinib (CEP-701), neratinib (HKI-272), nilotinib (TASIGNA®),semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib(PALLADIA®), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787, PTK/ZK),trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®),cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®),sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®),gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076,PCI-32765, AC220, dovitinib lactate (TK1258, CHIR-258), BIBW 2992(TOVOKTM®), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607,ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ-26483327, MGCD265,DCC-2036, BMS-690154, CEP 11981, tivozanib (AV-951), OSI-930, MM-121,XL-184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib(Velcade®)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779),everolimus (RAD-001), ridaforolimus, AP23573 (ARIAD), AZD8055(AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (SanofiAventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) andOSI-027 (OSI)), oblimersen, gemcitabine, caminomycin, leucovorin,pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone,dexamethasone, campathecin, plicamycin, asparaginase, aminopterin,methopterin, porfiromycin, melphalan, leurosidine, leurosine,chlorambucil, trabectedin, procarbazine, discodermolide,caminomycin-aminopterin, and hexamethyl melamine.

In some embodiments, the anti-cancer agent can be selected from, but notlimited to, one or more of the following anti-metabolite agents:5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium,carmofur, CibaGeigy CGP-30694, cyclopentyl cytosine, cytarabinephosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC,dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC,doxifluridine, Wellcome EHNA, Merck & Co. EX-015, fazarabine,floxuridine, fludarabine phosphate, 5-fluorouracil, N-(21-furanidyl)fluorouracil, Daiichi Seiyaku FO-152, isopropyl pyrrolizine, LillyLY-188011, Lilly LY-264618, methobenzaprim, methotrexate, WellcomeMZPES, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI NSC-39661, NCINSC-612567, Wamer-Lambert PALA, pentostatin, piritrexim, plicamycin,Asahi Chemical PL-AC, Takeda TAC788, thioguanine, tiazofurin, ErbamontTIF, trimetrexate, tyrosine kinase inhibitors, Taiho UFT and uricytin.

In some embodiments, the anti-cancer agent can be selected from, but notlimited to, one or more of the following alkylating-type agents: Shinogi254-S, aldo-phosphamide analogues, Altretamine, anaxirone, BoehringerMannheim BBR-2207, bestrabucil, budotitane, Wakunaga CA-102,carboplatin, carmustine, Chinoin-139, Chinoin-153, chlorambucil,cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233,cyplatate, Degussa D 384, Sumimoto DACHP(Myr)2, diphenylspiromustine,diplatinum cytostatic, Erba distamycin derivatives, Chugai DWA-2114R,ITI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium,fotemustine, Unimed G M, Chinoin GYKI-17230, hepsulfam, ifosfamide,iproplatin, lomustine, mafosfamide, mitolactolf Nippon Kayaku NK-121,NCI NSC-264395, NCI NSC-342215, oxaliplatin, Upjohn PCNU, prednimustine,Proter PTT-119, ranimustine, semustine, SmithKline SK&F-101772, YakultHonsha SN-22, spiromus-tine, Tanabe Seiyaku TA-077, tauromustine,temozolomide, teroxirone, tetraplatin and trimelamol.

In some embodiments, the anti-cancer agent can be selected from, but notlimited to, one or more of the following antibiotic-type agents: Taiho4181-A, aclarubicin, actinomycin D, actinoplanone, Erbamont ADR-456,aeroplysinin derivative, Ajinomoto AN 11, Ajinomoto AN3, Nippon Sodaanisomycins, anthracycline, azino-mycin-A, bisucaberin, Bristol-MyersBL-6859, Bristol-Myers BMY-25067, Bristol-Myers BNY-25551, Bristol-MyersBNY-26605, BristolMyers BNY-27557, Bristol-Myers BMY-28438, bleomycinsulfate, bryostatin-1, Taiho C-1027, calichemycin, chromoximycin,dactinomycin, daunorubicin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, KyowaHakko DC-88A, Kyowa Hakko, DC89-AJ, Kyowa Hakko DC92-B, ditrisarubicinB, Shionogi DOB-41, doxorubicin, doxorubicin-fibrinogen, elsamicin-A,epirubicin, erbstatin, esorubicin, esperamicin-A, esperamicin-Alb,Erbamont FCE21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482,glidobactin, gregatin-A, grincamycin, herbimycin, idarubicin, illudins,kazusamycin, kesarirhodins, Kyowa Hakko KM-5539, Kirin Brewery KRN-8602,Kyowa Hakko KT-5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, AmericanCyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin,mitoxantrone, SmithKline M-TAG, neoenactin, Nippon Kayaku NK-313, NipponKayaku NKT-01, SRI International NSC-357704, oxalysine, oxaunomycin,peplomycin, pilatin, pirarubicin, porothramycin, pyrindanycin A, TobishiRA-I, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin,Sumitomo SM5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A,sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SSPharmaceutical SS-9816B, steffimycin B, Taiho 4181-2, talisomycin,Takeda TAN-868A, terpentecin, thrazine, tricrozarin A, Upjohn U-73975,Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y-25024 andzorubicin.

In some embodiments, the anti-cancer agent can be selected from, but notlimited to, one or more of the following antineoplastic agents, inducingtubulin interacting agents, topoisomerase 11 inhibitors, topoisomerase Iinhibitors and hormonal agents: β-carotene, β-difluoromethyl-arginine,acitretin, Biotec AD-5, Kyorin AHC-52, alstonine, amonafide,amphethinile, amsacrine, Angiostat, ankinomycin, anti-neoplaston A10,antineoplaston A2, antineoplaston A3, antineoplaston A5. antineoplastonAS2-1F Henkel APD, aphidicolin glycinate, asparaginase, Avarol,baccharin, batracylin, benfluron, benzotript, Ipsen-Beaufour BIM-23015,bisantrene, BristoMyers BNY-40481, Vestar boron-10, bromofosfamide,Wellcome BW-502, Wellcome BW-773, caracemide, carmethizolehydrochloride, Ajinomoto CDAF, chlorsulfaquinoxalone, Chemes CHX-2053,Chemex CHX-100, Warner-Lambert CI-921, WamerLambert CI-937,Wamer-Lambert CI-941, Wamer-Lambert C1958, clanfenur, daviridenone, ICNcompound 1259, ICN compound 4711, Contracan, Yakult Honsha CPT-11,crisnatol, curaderm, cytochalasin B. cytarabine, cytocytin, Merz D-609,DABIS maleate, dacarbazine, datelliptinium, didemnin-B,dihaematoporphyrin ether, dihydrolenperone, dinaline, distamycin, ToyoPharmar DM-341, Toyo Pharmar DM-75, Daiichi Seiyaku DN-9693, docetaxelelliprabin, elliptiniurn acetate, Tsumura EPMTC, the epothilones,ergotamine, etoposide, etretinate, fenretinide, Fujisawa FR-57704tgallium nitrate, genkwadaphnin, Chugai GLA-43, Glaxo GR-63178, grifolanNMF5N, hexadecylphosphocholine, Green Cross HO-221, homoharringtonine,hydroxyurea, BTG ICRF-187, ilmofosine, isoglutamine, isotretinoin,Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECTCorp KI-8110, American Cyanamid L-623, leukoregulin, lonidamine,Lundbeck LU 1121 Lilly LY-186641, NCI (US) MAP, marycin, Merrel DowMDL-27048, Medco MEDR-340, merbarone, merocyanine derivatives,methylanilinoacridine, Molecular Genetics MGI136, minactivin,mitonafide, mitoquidone mopidamol, motretinide, Zenyaku Kogyo MST-16,N-(retinoyl)amino acids, Nisshin Flour Milling N-021,N-acylated-dehydroalanines, nafazatrom, Taisho NCU-190, nocodazolederivative, Normosang, NCI NSC-145813, NCI NSC-361456, NCI NSC-604782,NCI NSC-95580, ocreotide, Ono ONO-112, oquizanocine, Akzo Org-10172,paclitaxel, pancratistatin, pazelliptine, WamerLambert PD-111707,Wamer-Lambert PD-115934, Warner-Lambert PD-131141, Pierre Fabre PE-1001,ICRT peptide D, piroxantrone, polyhaematoporphyrin, polypreic acid,Efamol porphyrin, probimane, procarbazine, proglumide, Invitron proteasenexin I, Tobishi RA-700, razoxane, Sapporo Breweries RBS, restrictin-P,retelliptine, retinoic acid, Rhone-Poulenc RP-49532, Rhone-PoulencRP-56976, SmithKline SK&F-104864, Sumitomo SM-108, Kuraray SMANCS,SeaPharm SP10094, spatol, spirocyclopropane derivatives, spirogermanium,Unimed, SS Pharmaceutical SS-554, strypoldinone, Stypoldione, SuntorySUN 0237, Suntory SUN 2071, superoxide dismutase, Toyama T-506, ToyamaT-680, taxol, Teijin TEI-0303, teniposide, thaliblastine, Eastman KodakTJB-29, tocotrienol, topotecan, Topostin, Teijin TT82, Kyowa HakkoUCN-01, Kyowa Hakko UCN-1028, ukrain, Eastman Kodak USB-006, vinblastinesulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol,vinzolidine, withanolides and Yamanouchi YM.

In some embodiments, the additional therapeutic agent can be selectedfrom, but not limited to, acemannan, aclarubicin, aldesleukin,alemtuzumab, alitretinoin, altretamine, amifostine, aminolevulinic acid,amrubicin, amsacrine, anagrelide, anastrozole, ANCER, ancestim,ARGLABIN, arsenic trioxide, BAM 002 (Novelos), bexarotene, bicalutamide,broxuridine, capecitabine, celmoleukin, cetrorelix, cladribine,clotrimazole, cytarabine ociosfate, DA 3030 (Dong-A), daclizumab,denileukin diftitox, deslorelin, dexrazoxane, dilazep, docetaxel,docosanol, doxercalciferol, doxifluridine, doxorubicin, bromocriptine,carmustine, cytarabine, fluorouracil, HIT diclofenac, interferon alfa,daunorubicin, doxorubicin, tretinoin, edelfosine, edrecolomabeflornithine, emitefur, epirubicin, epoetin beta, etoposide phosphate,exemestane, exisulind, fadrozole, filgrastim, finasteride, fludarabinephosphate, formestane, fotemustine, gallium nitrate, gemcitabine,gemtuzumab zogamicin, gimeracil/oteracdil/tegafur combination,glycopine, goserelin, heptaplatin, human chorionic gonadotropin, humanfetal alpha fetoprotein, ibandronic acid, idarubicin, (imiquimod,interferon alfa, interferon alfa, natural, interferon alfa-2, interferonalfa-2a, interferon alfa-2b, interferon alfa-NI, interferon alfa-n3,interferon alfacon1, interferon alpha, natural, interferon beta,interferon beta-Ia, interferon beta-4b, interferon gamma, naturalinterferon gamma-Ia, interferon gamma-Ib, interleukin-I beta,iobenguane, irinotecan, irsogladine, lanreotide, LC 9018 (Yakult),leflunomide, lenograstim, lentinan sulfate, letrozole, leukocyte alphainterferon, leuprorelin, levamisole+fluorouracil, liarozole, lobaplatin,lonidamine, lovastatin, masoprocol, melarsoprol, metodopramide,mifepristone, miltefosine, mirimostim, mismatched double stranded RNA,mitoguazone, mitolactol, mitoxantrone, molgramostim, nafarelin,naloxone+pentazocine, nartograstim, nedaplatin, nilutamide, noscapine,novel erythropoiesis stimulating protein, NSC 631570 octreotide,oprelvekin, osaterone, oxaliplatin, paditaxel, pamidronic acid,pegaspargase, peginterferon alfa-2b, pentosan polysulfate sodium,pentostatin, picibanil, pirarubicin, rabbit antithymocyte polyclonalantibody, polyethylene glycol interferon alfa-2a, porfimer sodium,raloxifene, raltitrexed, rasburicase, rhenium Re 186 etidronate, RIIretinamide, rituximab, romurtide, samarium (153 Sm) lexidronam,sargramostim, sizofiran, sobuzoxane, sonermin, strontium-89 chloride,suramin, tasonermin, tazarotene, tegafur, temoporfin, temozolomide,teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropinalfa, topotecan, toremifene, tositumomab-iodine 131, trastuzumab,treosulfan, tretinoin, trilostane, trimetrexate, triptorelin, tumornecrosis factor alpha, natural, ubenimex, bladder cancer vaccine,Maruyama. vaccine, melanoma lysate vaccine, valrubicin, verteporfin,vinorelbine, VIRULIZIN, zinostatin stimalamer, or zoledronic acid;abarelix; AE 941 (Aetema), ambamustine, antisense oligonudeotide, bc-2(Genta), APC 8015 (Dendreon), cetuximab, decitabine,dexaminoglutethimide, diaziquone, EL 532 (Elan), EM 800 (Endorecherche),eniluracil, etanidazole, fenretinidel filgrastim SDO1 (Amgen),fulvestrant, galocitabine, gastrin 17 immunogen, HLA-B7 gene therapy(Vical), granulocyte macrophage colony stimulating factor, histaminedihydrochloride, ibritumomab tiuxetan, ilomastat, IM 862 (Cytran),intedeukin iproxifene, LDI 200 (Milkhaus), leridistim, lintuzumab, CA125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), HER-2and Fc MAb (Medarex), idiotypic 105AD7 MAb (CRC Technology), idiotypicCEA MAb (Trilex), LYM iodine 131 MAb (Technicone), polymorphicepithelial mucin-yttrium 90 MAb (Antisoma), marimastat, menogaril,mitumomab, motexafin, gadolinium, MX 6 (Galderma), nelarabine,nolatrexed, P 30 protein, pegvisomant, pemetrexed, porfiromycin,prinomastat, RL 0903 (Shire), rubitecan, satraplatin, sodiumphenylacetate, sparfosic acid, SRL 172 (SR Pharma), SU 5416 (SUGEN)y SU6668 (SUGEN), TA 077 (Tanabe), tetrathiomolybdate, thaliblastine,thrombopoietin, tin ethyl etiopurpurin, tirapazamine, cancer vaccine(Biomira), melanoma vaccine (New York University), melanoma vaccine(Sloan Kettering Institute), melanoma oncolysate vaccine (New YorkMedical College), viral melanoma cell lysates vaccine (Royal NewcastleHospital), or valspodar.

In some embodiments, the additional therapeutic agent can be selectedfrom, but not limited to, anti-cancer alkylating or intercalating agent(e.g., mechlorethamine, chlorambucil, Cyclophosphamide, Melphalan, andIfosfamide); antimetabolite (e.g., Methotrexate); purine antagonist orpyrimidine antagonist (e.g., 6-Mercaptopurine, 5-Fluorouracil,Cytarabile, and Gemcitabine); spindle poison (e.g., Vinblastine,Vincristine, Vinorelbine and Paditaxel); podophyllotoxin (e.g.,Etoposide, Irinotecan, Topotecan); antibiotic (e.g., Doxorubicin,Bleomycin and Mitomycin); nitrosourea (e.g., Carmustine, Lomustine);inorganic ion (e.g., Cisplatin, Carboplatin, Oxaliplatin or oxiplatin);enzyme (e.g., Asparaginase); hormone (e.g., Tamoxifen, Leuprolide,Flutamide and Megestrol); mTOR inhibitor (e.g., Sirolimus (rapamycin),Temsirolimus (CC1779), Everolimus (RAD001), AP23573 or other compoundsdisclosed in U.S. Pat. No. 7,091,213); proteasome inhibitor (such asVelcade, another proteasome inhibitor (see e.g., WO 02/096933) oranother NF-kB inhibitor, including, e.g., an IkK inhibitor); otherkinase inhibitors (e.g., an inhibitor of Src, BRC/Abl, kdr, flt3,aurora-2, glycogen synthase kinase 3 (“GSK-3”), EGF-R kinase (e.g.,Iressa, Tarceva, etc.), VEGF-R kinase, PDGF-R kinase, etc.); anantibody, soluble receptor or other receptor antagonist against areceptor or hormone implicated in a cancer (including receptors such asEGFR, ErbB2, VEGFR, PDGFR, and IGF-R; and agents such as Herceptin,Avastin, Erbitux, etc.); etc.

Examples of other therapeutic agents are noted elsewhere herein andinclude among others, Zyloprim, alemtuzmab, altretamine, amifostine,nastrozole, antibodies against prostate-specific membrane antigen (suchas MLN-591, MLN591RL and MLN2704), arsenic trioxide, bexarotene,bleomycin, busulfan, capecitabine, Gliadel Wafer, celecoxib,chlorambucil, cisplatin-epinephrine gel, cladribine, cytarabineliposomal, daunorubicin liposomal, daunorubicin, daunomycin,dexrazoxane, docetaxel, doxorubicin, Elliott's B Solution, epirubicin,estramustine, etoposide phosphate, etoposide, exemestane, fludarabine,5-FU, fulvestrant, gemcitabine, gemtuzumab-ozogamicin, goserelinacetate, hydroxyurea, idarubicin, idarubicin, Idamycin, ifosfamide,imatinib mesylate, irinotecan (or other topoisomerase inhibitor,including antibodies such as MLN576 (XR11576)), letrozole, leucovorin,leucovorin levamisole, liposomal daunorubicin, melphalan, L-PAM, mesna,methotrexate, methoxsalen, mitomycin C, mitoxantrone, MLN518 or MLN608(or other inhibitors of the fit-3 receptor tyrosine kinase, or PDFG-R),itoxantrone, paclitaxel, Pegademase, pentostatin, porfimer sodium,Rituximab (RITUXAN®), talc, tamoxifen, temozolamide, teniposide, VM-26,topotecan, toremifene, 2C4 (or other antibody which interferes withHER2-mediated signaling), tretinoin, ATRA, valrubicin, vinorelbine, orpamidronate, zoledronate or another bisphosphonate.

Exemplary biotherapeutic agents include, but are not limited to,interferons, cytokines (e.g., tumor necrosis factor, interferon α,interferon γ), vaccines, hematopoietic growth factors, monoclonalserotherapy, immunostimulants and/or immunodulatory agents (e.g., IL-1,2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) andantibodies (e.g. Herceptin (trastuzumab), T-DM1, AVASTIN (bevacizumab),ERBITUX (cetuximab), Vectibix (panitumumab), Rituxan (rituximab), andBexxar (tositumomab)).

In some embodiments, the chemotherapeutic agent can be selected fromHSP90 inhibitors. The HSP90 inhibitor can be a geldanamycin derivative,e.g., a benzoquinone or hygroquinone ansamycin HSP90 inhibitor (e.g.,IPI-493 and/or IPI-504). Non-limiting examples of HSP90 inhibitorsinclude IPI-493, IPI-504, 17-AAG (also known as tanespimycin orCNF-1010), BIIB-021 (CNF-2024), BIIB-028, AUY-922 (also known asVER-49009), SNX-5422, STA-9090, AT-13387, XL-888, MPC-3100, CU-0305,17-DMAG, CNF-1010, Macbecin (e.g., Macbecin I, Macbecin 11), CCT-018159,CCT 129397, PU-H71, or PF-04928473 (SNX-2112).

In some embodiments, the chemotherapeutic can be selected from PI3Kinhibitors. In some embodiments, the PI3K inhibitor can be an inhibitorof delta and gamma isoforms of PI3K. In some embodiments, the PI3Kinhibitor can be an inhibitor of alpha isoforms of PI3K. In otherembodiments, the PI3K inhibitor can be an inhibitor of one or morealpha, beta, delta and gamma isoforms of PI3K. Exemplary PI3K inhibitorsthat can be used in combination are described in, e.g., WO 09/088,990,WO 09/088,086, WO 2011/008302, WO 2010/036380, WO 2010/006086, WO09/114,870, WO 05/113556; US 2009/0312310, and US 2011/0046165.Additional PI3K inhibitors that can be used in combination include, butare not limited to, AMG-319, GSK 2126458, GDC-0980, GDC-0941, SanofiXL147, XL499, XL756, XL147, PF-46915032, BKM 120, CAL-101 (GS-1101), CAL263, SF1126, PX-886, and a dual PI3K inhibitor (e.g., Novartis BEZ235).

In some embodiments, provided herein is a method for using the acompound as provided herein, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein, in combination withradiation therapy in inhibiting abnormal cell growth or treating thehyperproliferative

disorder in the subject. Techniques for administering radiation therapyare known in the art, and these techniques can be used in thecombination therapy described herein. The administration of the compoundas provided herein in this combination therapy can be determined asdescribed herein.

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” as usedherein, refers to radiation therapy delivered by a spatially confinedradioactive material inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g., At-211,1-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner as provided herein include both solids and liquids. Byway of non-limiting example, the radiation source can be a radionuclide,such as 1-125, 1-131, Yb 169, Ir-192 as a solid source, 1-125 as a solidsource, or other radionuclides that emit photons, beta particles, gammaradiation, or other therapeutic rays. The radioactive material can alsobe a fluid made from any solution of radionuclide(s), e.g., a solutionof 1-125 or I-131, or a radioactive fluid can be produced using a slurryof a suitable fluid containing small particles of solid radionuclides,such as Au-198, Y-90. Moreover, the radionuclide(s) can be embodied in agel or radioactive micro spheres.

Without being limited by any theory, the compounds as provided herein,or a pharmaceutically acceptable form (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, or pharmaceutical compositions as provided herein,can render abnormal cells more sensitive to treatment with radiation forpurposes of killing and/or inhibiting the growth of such cells.Accordingly, provided herein is a method for sensitizing abnormal cellsin a subject to treatment with radiation which comprises administeringto the subject an amount of a compound as provided herein orpharmaceutically acceptable forms (e.g., pharmaceutically acceptablesalts, hydrates, solvates, isomers, prodrugs, and isotopically labeledderivatives) thereof, which amount is effective in sensitizing abnormalcells to treatment with radiation. The amount of the compound used inthis method can be determined according to the means for ascertainingeffective amounts of such compounds described herein.

The compounds as provided herein, or a pharmaceutically acceptable form(e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, orpharmaceutical compositions as provided herein, can be used incombination with an amount of one or more substances selected fromanti-angiogenesis agents, signal transduction inhibitors, andantiproliferative agents, glycolysis inhibitors, or autophagyinhibitors.

Anti-angiogenesis agents, such as MMP-2 (matrixmetalloproteinase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-11(cyclooxygenase 11) inhibitors, can be used in conjunction with acompound as provided herein and pharmaceutical compositions describedherein. Anti-angiogenesis agents include, for example, rapamycin,temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, andbevacizumab. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloproteinase inhibitors are described in WO 96/33172, WO 96/27583,European Patent Application No. 97304971.1, European Patent ApplicationNo. 99308617.2, WO 98/07697, WO 98/03516 (published Jan. 29, 1998), WO98/34918, WO 98/34915, WO 98/33768, WO 98/30566, European PatentPublication 606,046, European Patent Publication 931,788, WO 90/05719,WO 99/52910, WO 99/52889, WO99/29667, PCT International Application No.PCT/1B98/01113, European Patent Application No. 99302232.1, GreatBritain Patent Application No. 9912961.1, U.S. Provisional ApplicationNo. 60/148,464, U.S. Pat. Nos. 5,863,949, 5,861,510, and European PatentPublication 780,386, all of which are incorporated herein in theirentireties by reference. In some embodiments, MMP-2 and MMP-9 inhibitorsare those that have little or no activity inhibiting MMP-1. Otherembodiments include those that selectively inhibit MMP-2 and/or AMP-9relative to the other matrixmetalloproteinases (i.e., MAP-I, MMP-3,MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-II, MMP-12, and MMP-13).Some non-limiting examples of MMP inhibitors are AG-3340, RO 32-3555,and RS 13-0830.

Autophagy inhibitors include, but are not limited to, chloroquine,3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1,5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid,autophagy-suppressive algal toxins which inhibit protein phosphatases oftype 2A or type 1, analogues of cAMP, and drugs which elevate cAMPlevels such as adenosine, LY204002, N6-mercaptopurine riboside, andvinblastine. In addition, antisense or siRNA that inhibits expression ofproteins including, but not limited to ATG5 (which are implicated inautophagy), can also be used.

Medicaments which can be administered in conjunction with the compoundsas provided herein, or a pharmaceutically acceptable form (e.g.,pharmaceutically acceptable salts, hydrates, solvates, isomers,prodrugs, and isotopically labeled derivatives) thereof, include anysuitable drugs usefully delivered by inhalation for example, analgesics,(e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine);anginal preparations, (e.g., diltiazem; antiallergics, e.g.cromoglycate, ketotifen or nedocromil); anti-infectives, (e.g.,cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclinesor pentamidine); antihistamines, (e.g., methapyrilene;anti-inflammatories, e.g., beclomethasone, flunisolide, budesonide,tipredane, triamcinolone acetonide or fluticasone); antitussives, (e.g.,noscapine; bronchodilators, e.g., ephedrine, adrenaline, fenoterol,formoterol, isoprenaline, metaproterenol, phenylephrine,phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol,salmeterol, terbutalin, isoetharine, tulobuterol, oraprenaline or(−)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol);diuretics, (e.g., amiloride); anticholinergics (e.g., ipratropium,atropine or oxitropium); hormones, (e.g., cortisone, hydrocortisone orprednisolone); xanthines (e.g., aminophylline, choline theophyllinate,lysine theophyllinate or theophylline); and therapeutic proteins andpeptides, (e.g., insulin or glucagon). It will be clear to a personskilled in the art that, where appropriate, the medicaments can be usedin the form of salts (e.g., as alkali metal or amine salts or as acidaddition salts) or as esters (e.g., lower alkyl esters) to optimize theactivity and/or stability of the medicament.

Other exemplary therapeutic agents useful for a combination therapyinclude, but are not limited to, agents as described above, radiationtherapy, hormone antagonists, hormones and their releasing factors,thyroid and antithyroid drugs, estrogens and progestins, androgens,adxenocorticotropic hormone; adxenocortical steroids and their syntheticanalogs; inhibitors of the synthesis and actions of adrenocorticalhormones, insulin, oral hypoglycemic agents, and the pharmacology of theendocrine pancreas, agents affecting calcification and bone turnover:calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitaminssuch as water soluble vitamins, vitamin B complex, ascorbic acid, fatsoluble vitamins, vitamins A, K, and E, growth factors, cytokines,chemokines, muscarinic receptor agonists and antagonists;anticholinesterase agents; agents acting at the neuromuscular junctionand/or autonomic ganglia; catecholamines, sympathomimetic drugs, andadrenergic receptor agonists or antagonists; and 5-hydroxytryptamine(5-HT, serotonin) receptor agonists and antagonists.

Therapeutic agents can also include agents for pain and inflammationsuch as histamine and histamine antagonists, bradykinin and bradykininantagonists, 5-hydroxytryptamine (serotonin), lipid substances that aregenerated by biotransformation of the products of the selectivehydrolysis of membrane phospholipids, eicosanoids, prostaglandins,thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatoryagents, analgesic-antipyretic agents, agents that inhibit the synthesisof prostaglandins and thromboxanes, selective inhibitors of theinducible cyclooxygenase, selective inhibitors of the induciblecyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin,cytokines that mediate interactions involved in humoral and cellularimmune responses, lipid-derived autacoids, eicosanoids, [β-adrenergicagonists, ipratropium, glucocorticoids, methylxanthines, sodium channelblockers, opioid receptor agonists, calcium channel blockers, membranestabilizers and leukotriene inhibitors.

Additional therapeutic agents contemplated herein include diuretics,vasopressin, agents, agents affecting the renal conservation of water,rennin, angiotensin, agents useful in the treatment of myocardialischemia, anti-hypertensive agents, angiotensin converting enzymeinhibitors, [β-adrenergic receptor antagonists, agents for the treatmentof hypercholesterolemia, and agents for the treatment of dyslipidemia.

Other therapeutic agents contemplated herein include drugs used forcontrol of gastric acidity, agents for the treatment of peptic ulcers,agents for the treatment of gastroesophageal reflux disease, prokineticagents, antiemetics, agents used in irritable bowel syndrome, agentsused for diarrhea, agents used for constipation, agents used forinflammatory bowel disease, agents used for biliary disease, agents usedfor pancreatic disease. Therapeutic agents include, but are not limitedto, those used to treat protozoan infections, drugs used to treatMalaria, Amebiasis, Giardiasis, Trichomoniasis, Trypanosomiasis, and/orLeishmaniasis, and/or drugs used in the chemotherapy of helminthiasis.Other therapeutic agents include, but are not limited to, antimicrobialagents, sulfonamides, trimethoprim-sulfamethoxazole quinolones, andagents for urinary tract infections, penicillins, cephalosporins, andother β-Lactam antibiotics, an agent containing an aminoglycoside,protein synthesis inhibitors, drugs used in the chemotherapy oftuberculosis, mycobacteriumavium complex disease, and leprosy,antifungal agents, antiviral agents including norretroviral agents andantiretroviral agents.

Examples of therapeutic antibodies that can be combined with a subjectcompound include, but are not limited to, anti-receptor tyrosine kinaseantibodies (cetuximab, panitumumab, trastuzumab), anti CD20 antibodies(rituximab, tositumomab), and other antibodies such as alemtuzumab,bevacizumab, and gemtuzumab.

Moreover, therapeutic agents used for immunomodulation, such asimmunomodulators, immunosuppressive agents, tolerogens, andimmunostimulants are contemplated by the methods herein. In addition,therapeutic agents acting on the blood and the blood-forming organs,hematopoietic agents, growth factors, minerals, and vitamins,anticoagulant, thrombolytic, and antiplatelet drugs. Further therapeuticagents that can be combined with a subject compound can be found inGoodman and Gilman's “The Pharmacological Basis of Therapeutics” TenthEdition edited by Hardman, Limbird and Gilman or the Physician's DeskReference, both of which are incorporated herein by reference in theirentirety.

The compounds described herein can be used in combination with theagents provided herein or other suitable agents, depending on thecondition being treated. Hence, in some embodiments, the compounds asprovided herein will be co-administered with other agents as describedabove. When used in combination therapy, the compounds described hereincan be administered with the second agent simultaneously or separately.This administration in combination can include simultaneousadministration of the two agents in the same dosage form, simultaneousadministration in separate dosage forms, and separate administration.That is, a compound described herein and any of the agents describedabove can be formulated together in the same dosage form andadministered simultaneously. Alternatively, a compound as providedherein and any of the agents described above can be simultaneouslyadministered, wherein both the agents are present in separateformulations. In another alternative, a compound as provided herein canbe administered just followed by and any of the agents described above,or vice versa. In the separate administration protocol, a compound asprovided herein and any of the agents described above can beadministered a few minutes apart, or a few hours apart, or a few daysapart.

Administration of the compounds as provided herein can be effected byany method that enables delivery of the compounds to the site of action.An effective amount of a compound as provided herein can be administeredin either single or multiple doses by any of the accepted modes ofadministration of agents having similar utilities, including rectal,buccal, intranasal and transdermal routes, by intraarterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, as an inhalant, or via an impregnatedor coated device such as a stent, for example, or an artery-insertedcylindrical polymer.

When a compound as provided herein is administered in a pharmaceuticalcomposition that comprises one or more agents, and the agent has ashorter half-life than the compound as provided herein, unit dose formsof the agent and the compound as provided herein can be adjustedaccordingly.

EXAMPLES

The examples and preparations provided below further illustrate andexemplify the compounds as disclosed herein and methods of preparingsuch compounds. It is to be understood that the scope of the presentdisclosure is not limited in any way by the scope of the followingexamples and preparations. In the following examples, molecules with asingle chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers can be obtained by methods known to thoseskilled in the art.

The chemical entities described herein can be synthesized according toone or more illustrative schemes herein and/or techniques well known inthe art. Unless specified to the contrary, the reactions describedherein take place at atmospheric pressure, generally within atemperature range from about −10° C. to about 200° C. Further, except asotherwise specified, reaction times and conditions are intended to beapproximate, e.g., taking place at about atmospheric pressure within atemperature range of about −10° C. to about 200° C. over a period thatcan be, for example, about 1 to about 24 hours; reactions left to runovernight in some embodiments can average a period of about 16 hours.

The terms “solvent,” “organic solvent,” or “inert solvent” each mean asolvent inert under the conditions of the reaction being described inconjunction therewith including, for example, benzene, toluene,acetonitrile, tetrahydrofuran (“THF”), dimethytformamide (“DMF”),chloroform, methylene chloride (or dichloromethane “DCM”), diethylether, methanol, N-methylpyrrolidone (“NMP”), pyridine and the like.Unless specified to the contrary, for each gram of the limiting reagent,one cc (or mL) of solvent constitutes a volume equivalent.

Isolation and purification of the chemical entities and intermediatesdescribed herein can be effected, if desired, by any suitable separationor purification procedure such as, for example, filtration, extraction,crystallization, column chromatography, thin-layer chromatography orthick-layer chromatography, or a combination of these procedures. See,e.g., Carey et al. Advanced Organic Chemistry, 3^(rd) Ed., 1990 NewYork: Plenum Press; Mundy et al., Name Reactions and Reagents in OrganicSynthesis, 2^(nd) Ed., 2005 Hoboken, N.J.: J. Wiley & Sons. Specificillustrations of suitable separation and isolation procedures are givenby reference to the examples hereinbelow. However, other equivalentseparation or isolation procedures can also be used.

When desired, the (R)- and (S)-isomers of the nonlimiting exemplarycompounds, if present, can be resolved by methods known to those skilledin the art, for example by formation of diastereoisomeric salts orcomplexes which can be separated, for example, by crystallization; viaformation of diastereoisomeric derivatives which can be separated, forexample, by crystallization, gas-liquid or liquid chromatography;selective reaction of one enantiomer with an enantiomer-specificreagent, for example enzymatic oxidation or reduction, followed byseparation of the modified and unmodified enantiomers; or gas-liquid orliquid chromatography in a chiral environment, for example on a chiralsupport, such as silica with a bound chiral ligand or in the presence ofa chiral solvent. Alternatively, a specific enantiomer can besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer tothe other by asymmetric transformation.

The compounds described herein can be optionally contacted with apharmaceutically acceptable acid to form the corresponding acid additionsalts. Also, the compounds described herein can be optionally contactedwith a pharmaceutically acceptable base to form the corresponding basicaddition salts.

In some embodiments, disclosed compounds can generally be synthesized byan appropriate combination of generally well known synthetic methods.Techniques useful in synthesizing these chemical entities are bothreadily apparent and accessible to those of skill in the relevant art,based on the instant disclosure. Many of the optionally substitutedstarting compounds and other reactants are commercially available, e.g.,from Aldrich Chemical Company (Milwaukee, Wis.) or can be readilyprepared by those skilled in the art using commonly employed syntheticmethodology.

The discussion below is offered to illustrate certain of the diversemethods available for use in making the disclosed compounds and is notintended to limit the scope of reactions or reaction sequences that canbe used in preparing the compounds provided herein. The skilled artisanwill understand that standard atom valencies apply to all compoundsdisclosed herein in genus or named compound form unless otherwisespecified.

The following abbreviations have the definitions set forth below:

-   Boc: tert-butyl carbonate-   2-BuOH: 2-butanol (sec-butyl alcohol)-   DABCO: 1,4-diazabicyclo[2.2.2]octane-   dba: dibenzylideneacetone-   DCE: 1,2-dichloroethane-   DCM: dichloromethane-   DCC: dicyclohexylcarbodiimide-   Diglyme: diethylene glycol dimethyl ether-   DIPEA: diisopropylethylamine-   DMAP: 4-(dimethylamino)pyridine-   DMF: N,N-dimethylformamide-   DMSO: dimethylsulfoxide-   dppe: ethylenebis(diphenylphosphine)-   dppf: 1,1′-bis(diphenylphosphino)ferrocene-   dppp: 1,3-bis(diphenylphosphino)propane-   EDCl: N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride-   EtOAc: ethyl acetate-   EtOH: ethanol-   Glyme: 1,2-dimethoxyethane-   HATU:    1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxid hexafluorophosphate-   HBTU: N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl)uronium    hexafluorophosphate-   HMDS: hexamethyldisilizane-   HOBt: 1-hydroxybenzotriazole hydrate-   IPA: iso-propanol-   MeCN: acetonitrile-   MeOH: methanol-   2-MeTHF: 2-methyltetrahydrofuran-   MsCl: methanesulfonyl chloride-   NMR: nuclear magnetic resonance-   PPh₃: triphenylphosphine-   PTSA: p-toluenesulfonic acid monohydrate-   TBTU: N,N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)uronium    tetrafluoroborate-   TFA: trifluoroacetic acid-   THF: tetrahydrofuran-   T3P: propylphosphonic anhydride-   XantPhos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

General Synthetic Methods

In one embodiment, the compound of Formula I-1 can be combined with acompound of Formula I-2 to form a compound of Formula II-1:

wherein:

A is selected from

-   -   X₁ is selected from N and CR₁;    -   X₂ is selected from N and CR₂;    -   each X₄ is independently selected from N and CR₇;    -   X₅ is selected from N and CR;    -   X₆ is selected from N and CR₉;    -   R₁ is selected from H, acyl, alkyl, alkenyl, alkynyl, alkoxy,        aryloxy, alkoxycarbonyl, amido, amino, carbonate, carbamate,        carbonyl, carboxyl, ester, halo, CN, NO₂, hydroxy, phosphate,        phosphonate, phosphinate, phosphine oxide, mercapto, thio,        alkylthio, arylthio, thiocarbonyl, sulfonyl, sulfonamidyl,        sulfoxyl, sulfonate, urea, cycloalkyl, heterocyclyl, aryl, and        heteroaryl, each of which is substituted with 0, 1, 2, or 3 R₁₂;    -   each R₇ is independently selected from H, alkyl, alkenyl,        alkynyl, alkoxy, amido, amino, carbonyl, ester, halo, CN, and        NO₂, each of which is substituted with 0, 1, 2, or 3 R₁₂; and        wherein any two adjacent R₇ groups can be taken together with        the carbon atoms to which they are attached to form a        cycloalkyl, heterocyclyl, aryl, or heteroaryl ring, each of        which is substituted with 0, 1, 2, or 3 R₁₂;    -   R₈ is selected from H, acyl, alkyl, amido, amino, carbamate,        carbonyl, and urea, each of which is substituted with 0, 1, 2,        or 3 R₁₂;    -   R₉ is selected from H, alkyl, alkenyl, alkynyl, alkoxy, amino,        amido, ester, halo, CN, NO₂, cycloalkyl, heterocyclyl, aryl, and        heteroaryl, each of which is substituted with 0, 1, 2, or 3 R₁₂;        and    -   each R₁₂ is independently selected from acyl, alkyl, alkenyl,        alkynyl, alkoxy, aryloxy, alkoxycarbonyl, amido, amino,        carbonate, carbamate, carbonyl, ester, halo, CN, NO₂, hydroxyl,        phosphate, phosphonate, phosphinate, phosphine oxide, thio,        alkylthio, arylthio, thiocarbonyl, sulfonyl, sulfonamidyl,        sulfoxyl, sulfonate, urea, cycloalkyl, heterocycloalkyl, aryl,        and heteroaryl.

In some embodiments, X₁ can be CR₁, and X₂ can be N. In one embodiment,X₂ can be N, and R₁ can be selected from amido and ester. In anotherembodiment, X₂ can be N, and R₁ can be selected from H, alkyl, ester,halo, CN, and heteroaryl. In some embodiments, A can be

In other embodiments, X₁ can be selected from

Compounds of Formulae I-1 and 1-2 can be coupled using a metal-catalyzedprocess, such as, but not limited to, those in Price and Nachtsheim(Price Organic Reactions. 2011:1-82; Nachtsheim Beilstein J. Org. Chem.2010; 6:1-24). Non-limiting examples of a metal catalyst include AlCl₃and FeCl₃. In one embodiment, the metal catalyst can be AlCl₃. The ratioof equivalents of the metal catalyst relative to that of the compound ofFormula I-1 can range from about 0.75 to about 2.50, such as about 0.75to about 1.30, such as about 0.90 to about 1.30, such as about 1.50 toabout 2.50, such as about 1.75 to about 2.25, and further such as about1.05 to about 1.15. The equivalents of the compound of Formula I-2relative to that of the compound of Formula I-1 can range from about0.75 to about 3.0, such as about 1.5 to about 3.0, such as about 1.5 toabout 2.5, such as about 0.75 to about 1.50, such as about 0.75 to about1.25, and further such as about 1.75 to about 2.25.

Reaction times can vary from about 1 h to about 5 h, such as about 2 hto about 5 h, and further such as about 2 h to about 4 h, to convertcompounds of Formulae I-1 and I-2 to the compound of Formula II-1.Reaction temperatures can range from about 40° C. to about 120° C., suchas about 60° C. to about 100° C., such as about 50° C. to about 60° C.,and further such as about 70° C. to about 90° C. Suitable solventsinclude, but are not limited to, THF, DCE, glyme, dioxane and diglyme.In some embodiments, DCE can be the solvent. In other embodiments, glymeis the solvent.

Step b): Formation of III-1 from II-1 and II-2

In one embodiment, the compound of Formula II-1 can be combined with acompound of Formula II-2 to form a compound of Formula II-1:

wherein: for the compounds of Formula II-1, II-2 and III-1,

X₃ is selected from N and CR₄;

R₃ and R₄ are each independently selected from H, alkyl, alkoxy, halo,CN, and NO₂, each of which is substituted with 0, 1, 2, or 3 R₁₂: R₄ andR₅ can be taken together with the carbon atoms to which they areattached to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl group,each of which is substituted with 0, 1, 2, or 3 R₁₂;

R₅ is selected from H, alkyl, alkenyl, alkynyl, —NR₁₀R₁₁, —OR₁₁, and—SR₁₁, each of which is independently substituted with 0, 1, 2, or 3R₁₂; or when R₅ is —NR₁₀R₁₁, then R₁₀ and R₁₁ can be taken together withthe nitrogen atom to which they are attached to form a heterocyclyl orheteroaryl group, each of which is substituted with 0, 1, 2, or 3 R₁₂;and

the variables A, X₁, X₂, X₄, X₅, X₆, R₁, R₂, R₇, R₈, R₁₀, R₁₁, and R₁₂are as disclosed above and herein.

In some embodiments, X₁ can be CR₁, and X₂ can be N. In one embodiment,X₂ can be N, R₁ can be selected from amido and ester, and R₃ can bealkoxy. In another embodiment, X₂ can be N, R₃ can be alkoxy, and R₁ canbe selected from H, alkyl, ester, halo, CN, and heteroaryl. In anotherembodiment, R₅ can be selected from halo and —NR₁₀R₁₁. In someembodiments, A can be

In other embodiments, X₁ can be selected from

Compounds of Formulae II-1 and II-2 can be combined using a Pd-catalyzedprocess, such as, but not limited to, those described in Hartwig(Hartwig et al. J. Am. Chem. Soc. 2006; 128:3584-3591). Non-limitingexamples of Pd-catalysts include Pd(OAc)₂ and XantPhos, Pd₂dba₃ andXantPhos, and PdCl₂(dppf). In one embodiment, the Pd-catalyst isPd(OAc)₂ and XantPhos. The ratio of equivalents of the Pd-catalystcatalyst relative to that of the compound of Formula II-1 can range fromabout 0.05 to about 0.30, such as about 0.10 to about 0.25, and furthersuch as about 0.20 to about 0.30. Suitable bases for this processinclude, but are not limited to, Cs₂CO₃, NaOtBu, LiHMDS, K₃PO₄, K₂CO₃,NaOMe, and KOH. In one embodiment, the base is Cs₂CO₃. The ratio ofequivalents of base relative to that of the compound of Formula II-1 canrange from about 1.0 to about 1.5, such as about 1.1 to about 1.3, andfurther such as about 1.15 to about 1.25. The ratio of equivalents ofthe compound of Formula II-2 to that of the compound of Formula II-1 canrange from about 1.0 to about 1.5, such as about 1.2 to about 1.4, andfurther such as about 1.25 to about 1.35.

Non-limiting exemplary solvents for this process includes DMF, toluene,dioxane and DME. In one embodiment, the solvent is DMF. Reaction timescan vary from about 1 h to about 24 h, such as about 8 h to about 20 h,and further such as about 14 h to about 18 h to afford the compound ofFormula III-1. Reaction temperatures can range from about 50° C. toabout 150° C., such as about 75° C. to about 125° C., and further suchas about 90° C. to about 110° C.

In some embodiments, compounds of Formulae II-1 and II-2 can be combinedusing an acid-catalyzed process. Non-limiting examples of acid catalystsinclude PTSA, TFA and HCl. In one embodiment, the acid catalyst is PTSA.Non-limiting examples of solvents for this process include dioxane, THFand sec-butanol. In one embodiment, the solvent is dioxane. In anotherembodiment, the solvent is sec-butanol. The ratio of equivalents of thecompound of Formula II-2 to that of the compound of Formula II-1 canrange from about 1.0 to about 3.0, such as about 1.5 to about 2.5, andfurther such as about 1.75 to about 2.25. The ratio of equivalents ofthe acid relative to that of the compound of Formula II-1 can range fromabout 2.0 to about 4.0, such as about 2.5 to about 3.5, and further suchas about 2.75 to about 3.25. Reaction temperatures for this process canrange from about 50° C. to about 150° C., such as about 75° C. to about125° C., and further such as about 90° C. to about 110° C. Reactiontimes can vary from about 1 h to about 24 h, such as about 8 h to about20 h, and further such as about 14 h to about 18 h to afford thecompound of Formula III-1.

Additionally, compounds of Formulae II-1 and II-2 can be combined usinga base-mediated process. Non-limiting examples of bases includepotassium carbonate, sodium carbonate, cesium carbonate, and potassiumphosphate. In one embodiment, the base is potassium carbonate. Anon-limiting list of solvents includes MeCN, DMF, dioxane, and THF. Insome embodiments, the solvent is MeCN. The ratio of equivalents of thecompound of Formula II-1 to that of the compound of Formula II-2 canrange from about 0.75 to about 1.25, such as about 0.90 to about 1.10,and further such as about 0.95 to about 1.05. In one embodiment, theratio of equivalents of the compound of Formula II-1 to that of thecompound of Formula II-2 is from about 0.95 to about 1.05. The ratio ofthe equivalents of base to that of the compound of Formula II-1 or 11-2can range from about 5 to about 1.5, such as about 5 to about 2, such asabout 3.5 to about 2, such as about 3.5 to about 2.5, and further suchas about 3.25 to about 2.75. In some embodiments, the ratio of theequivalents of base to that of the compound of Formula III-1 or 11-2 canrange from about 3.25 to about 2.75. Reaction temperatures for thisprocess can range from about 50° C. to about 150° C., such as about 75°C. to about 125° C., such as about 75° C. to about 85° C., and furthersuch as about 90° C. to about 110° C. Reaction times can vary from about1 h to about 24 h, such as about 8 h to about 20 h, and further such asabout 14 h to about 18 h to afford the compound of Formula III-1.

Step c1): Formation of IV-1 from III-1 and HNR₁₀R₁₁

In one embodiment, a compound of Formula III-1 can be combined withHNR₁₀R₁₁ to form a compound of Formula IV-1:

wherein:

for the compound of Formula III-1, R₅ is halo; and

for the compounds of Formula III-1 and IV-1, the variables A, X₁, X₂,X₃, X₄, X₅, X₆, R₁, R₂, R₃, R₄, R₅, R₇, R₇, R₉, R₁₀, R₁₁, and R₁₂ are asdisclosed above and herein.

In one embodiment, X₁ can be CR₁, X₂ can be N, R₃ can be alkoxy. Inanother embodiment, X₂, can be N, R₃ can be alkoxy, and X₄ can be CR₄,where R₄ is H. In some embodiments R₁₀ is alkyl, and R₁₁ is alkylsubstituted with one R₁₂, and R₁₂ is amino. In some embodiments, A canbe

In other embodiments, X₁ can be selected from

The reaction can be performed in the presence of a base, such as, butnot limited to, K₂CO₃, Na₂CO₃, K₃PO₄, Cs₂CO₃, NaOtBu, KOtBu, NaOH, andKOH. In one embodiment, K₂CO₃ is the base. The ratio of equivalents ofthe base relative to that of the compound of Formula III-1 can rangefrom about 1 to about 4, such as about 2 to about 4, and further such asabout 3 to about 4. In some embodiments, the ratio of equivalents of thebase relative to that of the compound of Formula III-1 can be about 3.5to about 4.

The ratio of equivalents of HNR₁₀R₁₁ relative to that of the compound ofFormula III-1 can range from about 1 to about 4, such as about 1.5 toabout 3.5, such as about 2 to about 3, and further such as about 2.5 toabout 2.75. In one embodiment, the ratio of equivalents of HNR₁₀R₁₁relative to that of the compound of Formula III-1 can be about 2.5 toabout 2.75. Suitable solvents include, but are not limited to, THF,2-MeTHF, MeCN, DMF and sec-butanol. In one embodiment, the solvent isMeCN. In another embodiment, the solvent is DMF. Reaction times can varyfrom about 1 h to about 24 h, such as about 2 h to about 12 h, andfurther such as about 4 h to about 8 h. In one embodiment, the reactiontime is about 1 h to about 3 h. Reaction temperatures can vary fromabout 50° C. to about 120° C., such as about 60° C. to about 80° C.,such as about 80° C. to about 120° C., and further such as about 95° C.to about 105° C.

Step C2): Formation of IV-2 from III-1 and HOR₁₁

In one embodiment, a compound of Formula III-1 can be combined withHOR₁₁ to form a compound of Formula IV-2:

wherein:

for the compound of Formula III-1, R₅ is halo; and

for the compounds of Formula III-1 and IV-2, the variables A, X₁, X₂,X₃, X₄, X₅, X₆, X₇, R₁, R₂, R₃, R₄, R₅, R₇, R₈, R₉, R₁₁, and R₁₂ are asdisclosed above and herein.

In one embodiment, X₁ can be CR₁ and X₂ can be N. In another embodiment,X₂ can be N, R₃ can be alkoxy, and X₃ can be CR₄, where R₄ is H. Inanother embodiment, R₁₁ can be alk substituted with one R₁₂, and R₁₂ isH. In some embodiments, A can be

In other embodiments, X₁ can be selected from

The reaction can be performed in the presence of a base, such as, butnot limited to, NaH, KH and LiH. In one embodiment, the base is NaH. Theratio of equivalents of the base relative to that of the compound ofFormula III-1 can range from about 1 to about 4, such as about 2 toabout 4, and further such as about 3 to about 4. In some embodiments,the equivalents of base relative to that of the compound of FormulaeIII-1 is about 2.75 to about 3.25.

The ratio of equivalents of HOR₁₁ relative to that of the compound ofFormulae III-1 can range from about 1 to about 2, such as about 1.2 toabout 1.8, and further such as about 1.5 to about 1.75. Suitablesolvents include, but are not limited to, THF, 2-MeTHF, DMF and dioxane.In one embodiment, the solvent is THF. In another embodiment, thesolvent is DMF. In one embodiment, the base and HOR₁₁ can be firstcombined and stirred at about 20° C. to about 25° C., for about 10 minto about 15 min. Then, the compound of Formula III-1 is added. Whenaddition is complete, the reaction time can vary from about 1 h to about24 h, such as about 2 h to about 20 h, such as about 12 h to about 18 h,and further such as about 8 h to about 20 h. Reaction temperatures canvary from about 30° C. to about 80° C., such as about 40° C. to about60° C., and further such as about 45° C. to about 55° C.

Step d): Formation of V-1 from III-1, IV-1, or IV-2

In one embodiment, a compound of any one of Formulae III-1. IV-1, orIV-2can be converted to a compound of Formula V-1:

wherein:

for a compound of any one of Formulae III-1, IV-1, IV-2 and V-1, thevariables A, X₁, X₂, X₃, X₄, X₅, X₆, X₇, R₁, R₂, R₃, R₄, R₅, R₇, R₈, R₉,R₁₀, R₁₁, and R₁₂ are as defined above.

In some embodiments, X₁ can be CR₁, where R₁ is amido or ester. In oneembodiment, X₂ can be N and R₅ can be selected from —NR₁₀R₁₁ and —OR₁₁.In another embodiment, X₂ can be N, R₃ can be alkoxy, and X₃ can be CR₄,where R₄ is H. In some embodiments, A can be

In other embodiments, X₁ can be selected from

In one embodiment, the conversion of the compound of any one of FormulaeIII-1, IV-1, or IV-2 to the compound of Formula V-1 can occur throughthe hydrogenation of the nitro group to give the amino group of thecompound of Formula V-1. In the presence of H₂, suitable hydrogenationcatalysts include, but are not limited to, Raney Ni, Pd(OH)₂, PtO₂, andPd/C. In one embodiment, Pd/C is the hydrogenation catalyst. Thehydrogenation catalyst loading can be selected from about 2% Pd/C, about4% Pd/C, about 6% Pd/C, about 8% Pd/C, about 15% Pd/C, and about 20%Pd/C. In one embodiment, the hydrogenation catalyst loading is about 10%Pd/C. The ratio of equivalents of the hydrogenation catalyst to that ofthe compound of Formulae III-1, IV-1, or IV-2can be from about 0.01 toabout 0.25, such as about 0.05 to about 0.15, and further such as about0.05 to about 0.20. In one embodiment, the ratio of the hydrogenationcatalyst to that of the compound of Formulae III-1, IV-1, or IV-2 isabout 0.075 to about 0.125. In another embodiment, the ratio of thehydrogenation catalyst to that of the compound of Formulae III-1, IV-1,or IV-2 can be about 0.125 to about 0.175.

In another embodiment, the conversion of the compound of Formula III-1,IV-1, or IV-2 to a compound of Formula V-1 can occur through thereduction of the nitro group to afford the V-1 amino group by employingan oxidizable metal and a proton source. Examples of oxidizable metalsinclude, but are not limited to, iron, stannous chloride, zinc, andRaney nickel. Non-limiting examples of proton sources includehydrochloric acid, acetic acid, formic acid, and ammonium chloride. Inone embodiment, the oxidizable metal is zinc. In another embodiment, theproton source is ammonium chloride. Exemplary combinations can includeiron and hydrochloric acid, stannous chloride and hydrochloric acid,zinc and ammonium chloride, and Raney nickel and formic acid. The ratioof equivalents of the compound of Formulae III-1, IV-1, or IV-2 to thatof the zinc metal can be from about ¼ to about 1/10, such as about ¼ toabout ⅛, such as about ⅙ to about 1/10, and further such as about ⅕ toabout 1/7. The ratio of equivalents of the compound of Formulae III-1,IV-1, or IV-2 to that of ammonium chloride can be from about ⅙ to about1/18, such as about ⅙ to about 1/10, such as about ⅛ to about 1/18, suchas about 1/10 to about 1/18, such as about ⅛ to about 1/16, and furthersuch as about ⅛ to about 1/12.

Reaction times can vary from about 10 min to about 24 h, such as about30 min to about 4 h, such as about 30 min to about 2 h, such as about 2h to about 20 h, such as about 15 min to about 4 h, such as about 15 minto about 2 h, such as about 15 min to about 1 h, and further such asabout 15 min to about 45 min. Suitable solvents include, but are notlimited to, acetone, MeOH, THF, EtOH, DMF, and EtOAc. Suitable solventmixtures include, but are not limited to, acetone/water, MeOH/water,THF/water, EtOH/water, DMF/water and EtOAc/water. In some embodiments,the solvent mixture can be selected from acetone/water and MeOH/water.In one embodiment, the solvent mixture is acetone/water. Reactiontemperatures can vary from about 15° C. to about 50° C., such as about15° C. to about 40° C., such as about 15° C. to about 35° C., such asabout 15° C. to about 30° C., such as about 20° C. to about 30° C., andfurther such as about 20° C. to about 25° C.

Step e): Formation of I from V-1 and V-2 or V-3

In one embodiment, a compound of Formula V-1 can be combined with acompound of either Formula V-2 or V-3 to form a compound of Formula I:

wherein:

for the compound of any one of Formulae V-2, V-3, or I, R₆ can beselected from H, acyl, alkyl, amino, halo, CN, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl, each of which is substitutedwith 0, 1, 2, or 3 R₁₂; and for a compound of any one of Formulae V-1,V-2, V-3, and I, the variables A, X₁, X₂, X₃, X₄, X₅, X₆, X₇, R₁, R₂,R₃, R₄, R₅, R₇, R₈, R₉, R₁₀, R₁₁, and R₁₂ are as defined above.

In some embodiments, X₁ can be CR₁, where R₁ is amido or ester. In oneembodiment, X₂ can be N and R can be selected from —NR₁₀R₁₁ and —OR₁₁.In another embodiment, X₂ can be N, R₃ can be alkoxy, and X₃ can be CR₄,where R₄ is H. In other embodiments, Re can be H. In some embodiments, Acan be

In other embodiments, X₁ can be selected from

In one embodiment, the compounds of Formulae V-1 and V-2 can be combinedusing a coupling reagent and a base to form a compound of Formula I.Examples of coupling reagents include, but are not limited to, DCC,EDCI, HATU, HBTU, TBTU, and T3P. In one embodiment, the coupling reagentis EDCI. The ratio of equivalents of the coupling reagent to that of thecompound of Formula V-1 can range from about 1.75 to about 2.25, such asabout 1.75 to about 2.0, such as about 1.90 to about 2.25, and furthersuch as about 1.95 to about 2.05. Non-limiting examples of bases includepiperidine, triethylamine, diisopropylamine, and diisopropylethylamine.In one embodiment, the base is triethylamine. The ratio of the base tothat of the compound of Formula V-1 can range from about 0.75 to about3.5, such as about 1 to about 3, such as about 1.5 to about 2.5, andfurther such as about 1.75 to about 2.25. In one embodiment, the ratioof the base to that of the compound of Formula V-1 is about 1.75 toabout 2.25.

A coupling catalyst can optionally be added to the reaction. In oneembodiment, a coupling catalyst is added to the combination. In anotherembodiment, no coupling catalyst is added to the combination. Suitablecoupling catalysts include, but are not limited to, pyridine,N-methylimidazole, imidazole, DABCO, 4-(dimethylamino)pyridine, and4-(pyrrolidino)pyridine. A non-limiting example of a suitable couplingcatalyst is 4-(dimethylamino)pyridine. The ratio of equivalents of thecoupling catalyst to that of the compound of Formula V-1 can range fromabout 0.01 to about 0.25, such as about 0.01 to about 0.20, such asabout 0.05 to about 0.15, and further such as about 0.05 to about 0.10.In one embodiment, the ratio of the coupling catalyst to that of thecompound of the compound of Formula V-1 ranges from about 0.05 to about0.10. The ratio of equivalents of the compound of Formula V-2 to that ofthe compound of Formula V-1 can range from about 1.75 to about 2.25,such as about 1.75 to about 2.0, such as about 1.90 to about 2.25, andfurther such as about 1.95 to about 2.05. In one embodiment, the ratioof equivalents of the compound of Formula V-2 to that of the compound ofFormula V-1 ranges from about 1.95 to about 2.05.

Reaction times can vary from about 15 min to about 24 h, such as about15 min to about 2 h, such as about 6 h to about 8 h, such as about 8 hto about 16 h, and further such as about 16 h to about 24 h. Reactiontemperatures can vary from about 15° C. to about 50° C., such as about15° C. to about 40° C., such as about 15° C. to about 35° C., such asabout 15° C. to about 30° C., such as about 20° C. to about 30° C., andfurther such as about 20° C. to about 25° C. Suitable solvents include,but are not limited to, DCM, DMF, THF, diethyl ether, MeCN, and EtOAc.In some embodiments, DCM is the solvent. In other embodiments, DMF isthe solvent.

In another embodiment, the compound of Formula V-1 can be combined witha compound of Formula V-3 to form a compound of Formula I. The compoundsof Formulae V-1 and V-3 can be combined in the presence of a base.Non-limiting examples of the base include diisopropylamine,triethylamine, piperidine and diisopropylethylamine. In someembodiments, the base is triethylamine. The ratio of equivalents of thecompound of Formula V-3 to that of the compound of Formula V-1 can rangefrom 0.75 to about 1.25, such as about 0.75 to about 1.0, such as about0.90 to about 1.25, and further such as about 0.95 to about 1.05. Insome embodiments, the ratio of the compound of Formula V-3 to that ofthe compound of Formula V-1 is about 0.95 to about 1.05.

Suitable solvents include, but are not limited to, DMF, DCM, THF, MeCN,pyridine, diethyl ether, and EtOAc. In one embodiment, the solvent isDCM. In another embodiment, the solvent is DMF. Reaction temperaturescan range from about −10° C. to about 25° C., such as about −10° C. toabout 10° C., such as about −5° C. to about 25° C., such as about −5° C.to about 10° C., such as about 20° C. to about 25° C., and further suchas about −5° C. to about 5° C. In some embodiments, the combinationincludes adding the compound of Formula V-3 to the compound of V-1. Insome embodiments, the reaction temperature can be about −5° C. to about5° C. until the compound of Formula V-3 addition is complete, and thenthe reaction temperature is adjusted to about 20° C. to about 25° C.Reaction times can vary from about 15 min to about 24 h, such as about15 min to about 2 h, such as about 30 min to about 1 h, such as about 6h to about 8 h, such as about 8 h to about 16 h, and further such asabout 16 h to about 24 h.

Step f): Formation of VI-1 from I and H_(m)Z

In some embodiments, a compound of Formula I can be combined with anacid of Formula H_(m)Z to form an acid addition salt of Formula VI-1:

wherein:

for the compound of any one of Formulae I and VI-1, the variables A, X₁,X₂, X₃, X₄, X₅, X₆, X₇, R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁,and R₁₂, are as disclosed above and herein;

Z is an anionic form of a Bronsted-Lowry acid;

m is 1, 2, or 3; and

n is 1, 2, or 3.

In some embodiments, X₁ can be CR₁, where R₁ is amido or ester. In oneembodiment, X₂ can be N and R can be selected from —NR₁₀R₁₁ and —OR₁₁.In another embodiment, X₂ can be N, R₃ can be alkoxy, and X₃ can be CR₄,where R₄ is H. In other embodiments, Re can be H. In some embodiments, Acan be

In other embodiments, X₁ can be selected from

As used herein, a “Bronsted-Lowry acid” is a compound that is able todonate one or more protons to an acceptor base. An “anionic form” of aBronsted-Lowry acid is the partially or fully deprotonated conjugatebase of a given Bronstead-Lowry acid. For example, compounds of FormulaI contain one or more nitrogen atoms that can serve as a base to accepta proton from a Bronsted-Lowry acid. The variable “n” serves to indicatethe range of compound of Formula I:acid stoichiometries. TheBronsted-Lowry acids themselves can contain one or more acidic protonsfor donation, which is signified by the variable “m”. Values for theacid (H_(m)Z)_(n) include, but are not limited to the following:

Z is Cl⁻ and m is 1;

Z is Br⁻ and m is 1;

Z is MeSO₂ ⁻ and m is 1;

Z is PhSO₂ ⁻ and m is 1;

Z is 4-methylphenylSO₂ ⁻ and m is 1;

Z is —OC(O)—C(O)O— and m is 2;

Z is —OC(O)—CH₂—C(O)O— and m is 2;

Z is

and m is 3;

Z is SO₄ ³⁻ and m is 3; and

Z is PO₄ ³⁻ and m is 3.

In some embodiments, Z is Cl⁻, m is 1, and n is 1 or 2. In otherembodiments, Z is Cl⁻, m is 1, and n is 1 or 2. In some embodiments, Zis MeSO₂ ⁻ , m is 1, and n is 1 or 2. In other embodiments, Z is

m is 1, and n is 1 or 2.

Non-limiting examples of “H_(m)Z” acids are described by Berge et al. inJ. Pharmaceutical Sciences (1977) 66:1-19, such as adipic acid, alginicacid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,sulfuric acid, boric acid, camphoric acid, camphorsulfonic acid, citricacid, cyclopentanepropionic acid, gluconic acid, dodecylsulfuric acid,ethanesulfonic acid, formic acid, fumaric acid, glucoheptonic acid,glycerophosphoric acid, gluconic acid, heptanoic acid, hexanoic acid,hydroiodic acid, 2-hydroxy-ethanesulfonic acid, lactobionic acid, lauricacid, dodecylsulfonic acid, malic acid, maleic acid, malonic acid,methanesulfonic acid, 2-naphthalenesulfonic acid, nicotinic acid, nitricacid, oleic acid, oxalic acid, palmitic acid, pamoic acid, petcinicacid, peroxymonosulfuric acid, 3-phenylpropionic acid, picric acid,pivalic acid, propionic acid, stearic acid, succinic acid, tartric acid,thiocyanic acid, p-toluenesulfonic acid, undecanoic acid, valeric acid,and the like. In one embodiment, non-limiting examples of “H_(m)Z”acids, where m is 1, include hydrochloric acid, methanesulfonic acid,hydrobromic acid, benzenesulfonic acid, tosic acid, and the like. Inanother embodiment, non-limiting examples of “H_(m)Z” acids, where m canbe an integer greater than 1, include oxalic acid (m is 2), phosphoricacid (m is 3), citric acid (m is 3), malonic acid (m is 2), sulfuricacid (m is 2), and the like. Non-limiting examples of acid additionsalts of Formula V-1 include adipate, alginate, ascorbate, aspartate,benzenesulfonate, besylate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydrochloride, hydrobromide, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike.

In some embodiments, the compound of Formula I can be first dissolved orsuspended in a solvent. In some embodiments, the solvent can be analcohol, such as, but not limited to, MeOH, EtOH, IPA, or 2-BuOH. Inother embodiments, the solvent can be a non-alcoholic solvent, such as,but not limited to, DCM, EtOAc, THF, diethyl ether, acetone, heptane, oracetonitrile. In a further embodiment, the solvent can be a mixture oftwo or more of any of the aforementioned solvents.

After addition of the compound of Formula I to the solvent system, themixture can be heated to a temperature from about 30° C. to about 100°C., such as about 30° C. to about 75° C., such as about 50° C. to about100° C., such as about 35° C. to about 55° C., such as about 45° C. toabout 55° C., such as about 50° C. to about 75° C., and further such asabout 60° C. to 85° C. Subsequently, H_(m)Z can be added, neat or as amixture in a solvent, and the resulting mixture can be stirred fromabout 1 h to about 5 h, such as about 1 h to about 3 h, and further suchas about 1 h to about 2 h. The ratio of H_(m)Z to that of the compoundof Formula I can range from about 0.75 to about 3.5, such as about 1 toabout 3, such as about 1 to about 2, such as about 1 to about 1.5, suchas about 1 to about 1.25, such as about 1 to about 1.15, and furthersuch as about 0.95 to about 1.05. The mixture can then be cooled to atemperature from about −10° C. to about rt, such as about 0° C. to aboutrt, such as about 0° C. to about 10° C., and further such as about 15°C. to about rt. In one embodiment, the mixture can be cooled to aboutrt. A non-limiting example would be an initial temperature of thecompound of Formula I in a given solvent at about 55° C., addition ofH_(m)Z in a solvent, stirring for about 1.5 h and cooling to about rt.

Non-limiting methods of inducing crystallization include cooling,addition of an anti-solvent, scratching the crystallization vessel withan implement, by adding one or more seed crystals, or any combination ofthese methods. In one embodiment, the mixture can be cooled to inducecrystallization. In another embodiment, an anti-solvent can be added toinduce crystallization. In another embodiment, crystallization can beinduced by cooling and adding an anti-solvent. Non-limiting examples ofanti-solvents include heptane, hexane, pentane and dibutyl ether. In oneembodiment, heptane can be added. Upon crystallization, the mixture canbe filtered to isolate the compound of Formula VI-1. In someembodiments, the compound of Formula VI-1 can be isolated by decantingthe mother liquor, evaporation of volatile solvents in the mixture,solid-liquid centrifugation, and using a solid-phase crystallizationbase to induce crystallization followed by removal from the base. Thestoichiometry, n, of the resulting acid addition salt can be determinedby using any one of the many analytical methods known to a personskilled in the art such as, but not limited to, mass spectral analysis,elemental analysis, and NMR spectroscopy.

Exemplary Preparation Sequences for the Compound of Formula I

In one non-limiting embodiment, a compound of Formula I can be formedusing the following sequence of general method steps as described above:step a), step b), step ci), step d), and then step e). In anothernon-limiting embodiment, a compound of Formula I can be formed using thefollowing sequence of general method steps as described above: step a),step b), step c2), step d) and then step e). In a further non-limitingembodiment, a compound of Formula I can be formed using the followingsequence of general method steps as described above: step a), step b),step d), and then step e).

Intermediate A1 4-fluoro-2-methoxyaniline

To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (100 g, 0.584 mol) inMeOH (1.5 L) was added 10%-Pd/C (10 g). The mixture was stirred under ahydrogen atmosphere at rt overnight. Subsequently, the mixture wasfiltered and the filtrate was concentrated in vacuo to afford4-fluoro-2-methoxyaniline (A1) as a brown oil.

Intermediate A2 4-fluoro-2-methoxy-5-nitroaniline

To a concentrated sulfuric acid solution (800 mL) was added4-fluoro-2-methoxyaniline (A3) (79.4 g, 0.562 mol) at −10° C., thenguanidine nitrate (68.7 g, 0.562 mol) over the course of 1 h. Themixture was stirred at 0° C. for 2 h. Subsequently, the mixture wastreated with sodium bicarbonate until the pH was 7. The mixture was thenfiltered and the filtrate was extracted with DCM (5 L×2). The isolatedorganic layer was dried over sodium sulfate, filtered and concentratedin vacuo to afford 4-fluoro-2-methoxy-5-nitroaniline (A2) as a brownsolid.

Intermediate A3N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-2-nitrobenzene-1,4-diamine

4-Fluoro-2-methoxy-5-nitroaniline (A4) (2 g, 10.8 mmol) was combinedwith N1,N1,N2-trimethylethane-1,2-diamine (1.2 g, 11.8 mmol) andpotassium carbonate (3.0 g, 21.6 mmol) in MeCN (20 mL). The mixture wasstirred at 80° C. for 2 h. Upon cooling, the mixture was filtered andthe filtrate was concentrated in vacuo to affordN1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-2-nitrobenzene-1,4-diamine(A3) as a red oil.

Intermediate A4 (R)-1-(dimethylamino)-3-ethoxypropan-2-ol

Step 1: To a solution of (R)-(2-chloromethyl)oxirane (5 g, 54.1 mmol)and tetra-n-butylammonium bromide (870 mg, 5 mol-%) in EtOH (3.5 mL) wasadded sodium hydroxide (2.4 g) at 0° C. The mixture was then stirred atrt overnight. Subsequently, the mixture was filtered, washed with DCM,and the filtrate was concentrated in vacuo.

Step 2: The resulting residue was stirred with a solution ofdimethylamine in THF (30 mL, 2.0 M) at rt for 3 h. The mixture was thenconcentrated in vacuo and the resulting residue was purified by flashcolumn chromatography on silica gel (5% MeOH/DCM) to afford(R)-1-(dimethylamino)-3-ethoxypropan-2-ol as a colorless liquid.

The following intermediate compounds, as shown in Table 3, weresynthesized in analogous fashion to Step 2 of intermediate A4.

TABLE 3 Intermediate A Epoxide Amine

Intermediate A7 Isopropyl 2,4-dichloropyrimidine-5-carboxylate

A solution of 2,4-dichloropyrimidine-5-carbonyl chloride (2.00 g, 9.45mmol) in THF (4.7 mL) was cooled to −78° C. before IPA (0.80 mL) wasadded. The mixture was warmed to rt and stirred overnight. The mixturewas then concentrated in vacuo and purified by flash columnchromatography on silica gel (0%→10% EtOAc/heptane) to afford isopropyl2,4-dichloropyrimidine-5-carboxylate (A7) as a colorless oil.

Intermediate A8 7-methoxy-1-methyl-1H-indole

To a solution of 7-hydroxy-1H-indole (1.00 g, 7.5 mmol) in DMF (25 mL)was added potassium carbonate (5.19 g, 37.6 mmol), followed byiodomethane (1.40 mL, 22.5 mmol). The mixture was heated to 60° C. andstirred overnight. The mixture was then cooled to 0° C. and sodiumhydride (0.90 g, 22.5 mmol) was added. The mixture was warmed to rt andstirred for 10 min before adding additional iodomethane (1.40 mL, 22.5mmol). The resulting mixture was heated to 60° C. and stirred for anadditional 2 h. Upon cooling, the mixture was cooled to rt and dilutedwith water (50 mL) and EtOAc (50 mL). The layers were separated and theaqueous phase was extracted with EtOAc (3×50 mL). The combined organiclayers were washed with water (2×50 mL) and brine (50 mL), then driedover sodium sulfate, filtered, and concentrated under reduced pressureto afford 7-methoxy-1-methyl-1H-indole (A8).

Intermediate A9 N-(2,4-dichloropyrimidin-5-yl)-2,2,2-trifluoroacetamide

A solution of 5-amino-2,4-dichloropyrimidine (2.00 g, 12.2 mmol) in DCM(41 mL) was treated with trifluoroacetic anhydride (1.87 mL, 13.4 mmol).The resulting mixture was stirred at rt for 30 min, then concentrated invacuo. The resulting residue was suspended in heptane, filtered, andair-dried to affordN-(2,4-dichloropyrimidin-5-yl)-2,2,2-trifluoroacetamide (A9).

Intermediate A10 1H-indol-1-amine

To a solution of indole (5.7 g, 49 mmol) in DMF (100 mL) was addedsodium hydride (1.6 g, 60% mineral oil dispersion) at rt, and themixture was stirred for 1 h at rt. Subsequently, a solution ofchloramine in diethyl ether (320 mL) was added to the mixture, andstirred for 2 h at rt. To the resulting mixture was added aqueous sodiumthiosulfate, followed by water (100 mL). The mixture was extracted withDCM, and the combined organic layers were dried over magnesium sulfate,filtered, and concentrated in vacuo. The resulting residue was purifiedby flash column chromatography on silica gel (0→50% EtOAc/heptane) toafford 1H-indol-1-amine (A10) as brown solid.

Intermediate A11 N,N-dimethyl-1H-indol-1-amine

To a solution of 1H-indol-1-amine (A10) (2.64 g, 20 mmol) in DMF (20 mL)was added iodomethane (2.0 mL) and potassium carbonate (4.0 g), and theresulting mixture was stirred at rt for 2 days. Subsequently, themixture was filtered, and the filtrate was concentrated in vacuo. Theresulting residue was purified by flash column chromatography on silicagel (0→50% EtOAc/heptane) to afford N,N-dimethyl-1H-indol-1-amine (A11)as light brown solid.

Intermediate A12 1-ethyl-1H-indole

To a mixture of indole (1.17 g, 10 mmol) in DMF (10 mL) was added sodiumhydride (480 mg, 12 mmol, 60% dispersion in mineral oil), and themixture was stirred at rt for 30 min before adding iodoethane (0.96 ml,12 mmol) at 0° C. The mixture was stirred overnight before diluting withwater (20 mL). The resulting mixture was extracted with DCM (3×10 mL)and the combined organic layers were dried over magnesium sulfate,filtered, and concentrated in vacuo. The resulting residue was purifiedby flash column chromatography on silica gel (0→20% EtOAc/DCM) to afford1-ethyl-1H-indole (A12).

Intermediate A13 1-cyclopropyl-1H-indole

To a mixture of indole (585 mg, 5.0 mmol), cyclopropylboronic acid (860mg, 10 mmol), and sodium carbonate (1.06 g, 10 mmol), in DCE (20 mL),was added a suspension of 2,2′-bipyridine (781 mg, 5.0 mmol) andcopper(II) acetate (908 mg, 5.0 mmol), in DCE (15 mL), and the resultingmixture was stirred at 70° C. for 4h. Upon cooling, the mixture wasfiltered and the filtrate was concentrated in vacuo. The resultingresidue was purified by flash column chromatography on silica gel (0→25%EtOAc/heptane) to afford 1-cyclopropyl-1H-indole (A13) as yellow oil.

Intermediate A14 isopropyl(E)-4-(2-butoxyvinyl)-2-chloropyridine-5-carboxylate

A mixture of isopropyl 2,4-dichloropyrimidine-5-carboxylate (50 mg, 0.21mmol), 1-(vinyloxy)butane (63 mg, 0.63 mmol), palladium(II) acetate (4mg, 0.015 mmol), and TEA (0.032 mL), in PEG-400 (2 mL), was stirred at80° C. for 5 h. Upon cooling, the mixture was diluted with water andextracted with DCM. The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuo. The resulting residue waspurified by flash column chromatography on silica gel (0→10%EtOAc/heptane) to afford isopropyl(E)-4-(2-butoxyvinyl)-2-chloropyrimidine-5-carboxylate (A14).

Intermediate A15 isopropyl2-chloro-4-(imidazo[1,2-a]pyridin-3-yl)pyrimidine-5-carboxylate

To a mixture of isopropyl(E)-4-(2-butoxyvinyl)-2-chloropyrimidine-5-carboxylate (A14) (100 mg,0.37 mmol) in dioxane (3 mL) and water (1 mL), was added NBS (66 mg,0.37 mmol), and the resulting mixture was stirred at rt for 1 h beforeadding pyridin-2-amine (35 mg, 0.37 mmol). The mixture was then stirredat 85° C. for 2 h. Upon cooling, the mixture was diluted with water andextracted with EtOAc. The combined organic layers were dried over sodiumsulfate, filtered, and concentrated in vacuo. The resulting residue waspurified by flash column chromatography on silica gel (0→25% EtOAc/DCM)to afford isopropyl2-chloro-4-(imidazo[1,2-a]pyridin-3-yl)pyrimidine-5-carboxylate (A15) asa yellow solid.

Intermediate A16 6-(1-methyl-1H-pyrazol-4-yl)-1H-indole

A mixture of 6-bromo-1H-indole (300 mg, 1.53 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(478 mg, 2.3 mmol), tetrakis(triphenylphosphine)palladium(0) (92 mg,0.08 mmol), and potassium carbonate (2.3 g, 1.7 mmol), in DMF (3 mL),was stirred at 90° C. for 3 h. Upon cooling, the mixture was dilutedwith water and extracted with DCM. The combined organic layers weredried over magnesium sulfate, filtered, and concentrated in vacuo. Theresulting residue was purified by flash column chromatography on silicagel (0→50% EtOAc/heptane) to afford6-(1-methyl-1H-pyrazol-4-yl)-1H-indole (A16) as yellow solid.

Intermediate A17 (2,4-dimethoxypyrimidin-5-yl)dimethylphosphine oxide

A mixture of 5-iodo-2,4-dimethoxypyrimidine (2.26 g, 10 mmol),dimethylphosphine oxide (1.17 g, 15 mmol), palladium acetate (0.67 g,1.0 mmol), XPhos (1.16 g, 2.0 mmol), and cesium carbonate (4.9 g, 15mmol), in DMF (20 mL), was stirred at 60° C. for 1 h. Upon cooling, themixture was filtered, and the filtrate was concentrated in vacuo. Theresulting residue was purified by flash column chromatography on silicagel (15% MeOH/DCM) to afford(2,4-dimethoxypyrimidin-5-yl)dimethylphosphine oxide as white solid.

Intermediate A18 (2,4-dihydroxypyrimidin-5-yl)dimethylphosphine oxide

To a solution of (2,4-dimethoxypyrimidin-5-yl)dimethylphosphine oxide(A17) (140 mg, 0.65 mmol) in DCM (6 mL) was added TMSI (0.19 mL) at rt,and stirred for 0.5 h at rt. Subsequently, MeOH (0.4 mL) was added tothe mixture, and the resulting mixture was purified by flash columnchromatography on silica gel (20% MeOH/DCM) to afford(2,4-dihydroxypyrimidin-5-yl)dimethylphosphine oxide (A18) as whitesolid.

Intermediate A19 (2,4-dichloropyrimidin-5-)dimethylphosphine oxide

A mixture of (2,4-dihydroxypyrimidin-5-yl)dimethylphosphine oxide (A18)(0.6 g, 3.19 mmol) in phosphorus (V) oxychloride (5 mL) was stirred at140° C. for 3 h. Upon cooling, the mixture was poured onto ice andaqueous sodium bicarbonate was added. The mixture was extracted with DCMand the combined organic layers were concentrated in vacuo. Theresulting residue was purified by flash column chromatography on silicagel (10% MeOH/DCM) to afford(2,4-dichloropyrimidin-5-yl)dimethylphosphine oxide (A18) as yellowsolid.

Intermediate A20 1-Methyl-3-(tributylstannyl)-1H-indazole

To a mixture of 3-bromo-1-methyl-1H-indazole (1.00 g, 4.74 mmol) andtetrakis(triphenylphosphine)palladium(0) (0.55 g, 0.47 mmol), in1,4-dioxane (47 mL), was added hexabutylditin (4.78 mL, 9.48 mmol), andthe resulting mixture was stirred at 100° C. overnight. Upon cooling,aqueous potassium fluoride (1 M, 25 mL) was added, the mixture wasstirred at rt for 15 min and then filtered through a pad of Celite,before rinsing with EtOAc. The filtrate was washed with water (2×25 mL).The combined aqueous layers were extracted with EtOAc (50 mL), and thecombined organic layers were dried over magnesium sulfate, filtered, andconcentrated in vacuo. The resulting residue was purified by flashcolumn chromatography on silica gel (0→10% EtOAc/heptane) to afford1-methyl-3-(tributylstannyl)-1H-indazole (A20) as a clear, colorlessoil.

Intermediate A21 tert-Butyl3-(trimethylstannyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate

A mixture of tert-butyl 3-iodo-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(250 mg, 0.73 mmol) in THF (2.1 mL) was cooled to −78° C., before addingtrimethyltin chloride (724 mg, 3.63 mmol), followed by n-BuLi (2.5 M inhexanes, 0.87 mL, 2.18 mmol). The mixture was warmed to rt and stirredfor 6 h. Subsequently, MeOH was added and the resulting mixture wasconcentrated in vacuo. The resulting residue was purified by flashcolumn chromatography on silica gel (0→20% EtOAc/heptane) to affordtert-butyl 3-(trimethylstannyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate(A21) as a clear, colorless oil.

Intermediate 51 1-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)-1H-indole

To a solution of 2-(4-methylpiperazin-1-yl)ethanol (1.926 g, 13.38 mmol)in THF (10 mL) at 0° C. was added methanesulfonyl chloride (0.54 ml,13.38 mmol), and then stirred at rt for 2 h. To a solution of1-methyl-1H-indol-6-ol (390 mg, 2.67 mmol) in DMF (4 mL) was addedsodium hydride (192 mg, 8.0 mmol) at 0° C. and stirred for 30 min, andwas then added to the aforementioned THF solution at 0° C. The resultingmixture was stirred at rt overnight, and subsequently concentrated invacuo. The resulting residue was purified by flash column chromatographyon silica gel to afford1-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)-1H-indole (B1).

The following intermediate compounds, as shown in Table 4, weresynthesized in analogous fashion to intermediate B1.

TABLE 4 Intermediate B Alcohol Hydroxyindole

Intermediate C1 tert-butyl2-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-1-carboxylate

A flask charged with N-boc-2-indole boronic acid (3.00 g, 11.5 mmol),4-bromo-3,6-dihydro-2H-pyran (2.44 g, 14.5 mmol), andtetrakis(tripheylphosphine)palladium(0) (1.33 g, 1.15 mmol) wasevacuated and purged with nitrogen three times. 1,4-dioxane (38 mL) wasthen added, followed by a solution of sodium carbonate (2 M, 17.3 mL,34.6 mmol). The mixture was sparged with nitrogen, then stirred at 100°C. for 2 h. Upon cooling to rt, the mixture was diluted with EtOAc (50mL) and water (100 mL). The layers were separated and the aqueous phasewas extracted with EtOAc (3×50 mL). The combined organic layers werewashed with brine (100 mL), then dried over sodium sulfate, filtered,and concentrated in vacuo. The resulting residue was purified by flashcolumn chromatography on silica gel (0%→10% EtOAc/heptane) to affordtert-butyl 2-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-1-carboxylate (C1) asa yellow oil.

The following intermediate compounds, as shown in Table 5, weresynthesized in analogous fashion to intermediate C1.

TABLE 5 Intermediate C Bromide

Intermediate C5 2-(3,6-dihydro-2H-pyran-4-yl)-1H-indole

A solution of tert-butyl2-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-1-carboxylate (2.84 g, 9.5 mmol)in DCM (32 mL) was cooled to 0° C., and then treated with neat TFA (36.3mL, 474 mmol). The mixture was then stirred at rt for 1H. Subsequently,the mixture was cooled to 0° C. and aqueous sodium hydroxide (4N) wasadded until the mixture pH was greater than 10. The mixture was furtherdiluted with DCM. The layers were then separated, and the aqueous phasewas extracted with DCM (3×50 mL). The combined organics were then washedwith saturated sodium bicarbonate (75 mL) and brine (75 mL), then driedover sodium sulfate, filtered, and concentrated in vacuo. The resultingresidue was purified by flash column chromatography on silica gel(0%→30% EtOAc/heptane) to afford 2-(3,6-dihydro-2H-pyran-4-yl)-1H-indole(C5) as a pale orange solid.

The following compounds, as shown in Table 6, were prepared in analogousfashion to intermediate C5.

TABLE 6 Intermediate C Indole

Intermediate D12-(5-chloropyridin-3-yl)-3-(2-chloropyrimidin-4-yl)-1H-indole

A solution of 2-(5-chloropyridin-3-yl)-1H-indole (C6) (1.8 g, 7.78 mmol)in anhydrous DCE (15 mL) was cooled to 0° C., and methylmagnesiumbromide (4 mL, 2 M in THF) was added dropwise. The mixture was stirredat 0° C. for 10 min before 2,6-dichloropyrimidine (1.74 g, 11.66 mmol)was added and the resulting mixture was stirred at reflux for 14 h. Uponcooling to rt, MeOH (10 mL) was added to the mixture. The resultingmixture was concentrated in vacuo, and the resulting residue was dilutedwith DCM and water. The organic phase was isolated, dried over anhydroussodium sulfate, filtered, and concentrated in vacuo. The resultingresidue was then was purified by flash column chromatography on silicagel (0%→50% EtOAc/heptane) to afford2-(5-chloropyridin-3-yl)-3-(4-chloropyrimidin-2-yl)-1H-indole (D1) as ayellow solid.

The following compounds, as shown in Table 7, were prepared in analogousfashion to intermediate D1.

TABLE 7 Intermediate D Indole Pyrimidine/triazine

Intermediate E1 isopropyl2-chloro-4-(1H-indol-1-yl)pyrimidine-5-carboxylate

Indole (120 mg, 1 mmol) was dissolved in DMF (3 mL) and the mixture wastreated with sodium hydride (45 mg, 1.1 mmol, 60% dispersion in oil) at0° C. for 15 min. Isopropyl 2,4-dichloropyrimidine-5-carboxylate (A7)(220 mg, 1.1 mmol) was added to the mixture and the resulting mixturewas stirred at rt for 16 h. Subsequently, water was added and themixture was concentrated in vacuo. The resulting residue was dissolvedin EtOAc and water. The organic phase was isolated, dried over anhydroussodium sulfate, and concentrated in vacuo. The resulting residue wasthen purified by flash column chromatography on silica gel (0%→10%EtOAc/heptane) to afford methyl2-chloro-4-(1H-indol-1-yl)pyrimidine-5-carboxylate as a white solid.

The following compounds, as shown in Table 8, were prepared in analogousfashion to intermediate E1.

TABLE 8 Intermediate E Pyrimidine Indole

Intermediate F13-(2-chloro-5-ethylpyrimidin-4-yl)pyrazolo[1,5-a]pyridine

A solution of 5-ethyl-2,4-dichloropyrimidine (160 mg, 0.90 mmol),pyrazolo[1,5-a]pyridin-3-ylboronic acid pinacol ester (287 mg, 1.17mmol), and [1,1′-bis(diphenyl-phosphino)ferrocene]dichloropalladium(II)(40 mg, 0.054 mmol) in DMF (9.0 mL) was added, followed by aqueoussodium carbonate (2.0 mL, 4.0 mmol). The mixture was then heated to 100°C. and stirred for 14 h. Upon cooling, the mixture was concentrated invacuo, and the resulting residue was diluted with 20% (v/v) MeOH inEtOAc (5 mL) and filtered through a Celite pad with additional 20% (v/v)MeOH in EtOAc (20 mL). The filtrate was then concentrated in vacuo andthe resulting residue was purified by flash column chromatography onsilica gel (0%→5% MeOH/DCM) to afford3-(2-chloro-5-ethylpyrimidin-4-yl)pyrazolo[1,5-a]pyridine (F1) as awhite solid.

The following intermediate compounds, as shown in Table 9, weresynthesized in analogous fashion to intermediate F1.

TABLE 9 Intermediate F Boron reagent Pyrimidine

Intermediate F7 Isopropyl2-chloro-4-(1-methyl-1H-indazol-3-yl)pyrimidine-5-carboxylate

To a mixture of isopropyl 2,4-dichloropyrimidine-5-carboxylate (A7)(0.31 g, 1.32 mmol) and 1-methyl-3-(tributylstannyl)-1H-indazole (A20)(0.67 g, 1.59 mmol), in 1,4-dioxane (24 mL), was addedtris(dibenzylideneacetone)dipalladium(0) (0.60 g, 0.66 mmol). Theresulting mixture was stirred at 80° C. for 30 min. Upon cooling, themixture was concentrated in vacuo, and the resulting residue waspurified by flash column chromatography on silica gel (0→20%EtOAc/heptane) to afford isopropyl2-chloro-4-(1-methyl-1H-indazol-3-yl)pyrimidine-5-carboxylate (F7) as anoff-white solid.

The following intermediate compounds, as shown in Table 10, weresynthesized in analogous fashion to intermediate F7.

TABLE 10 Intermediate F Tin reagent Pyrimidine

Intermediate G1 Methyl2-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate

A solution of methyl 2,4-dichloropyrimidine-5-carboxylate (2.07 g, 10mmol) in DCE (15 mL) was cooled to 0° C. before aluminum chloride (2.7g, 20 mmol) was added. The resulting mixture was warmed to rt andstirred for 15 min before adding 1-methyl-indole (1.32 g, 10 mmol). Theresulting mixture was stirred at 55° C. for 1.5 h, then cooled to 0° C.MeOH (5 mL) and water (10 mL) were added, and the resulting mixture wasstirred at rt for 30 min. Additional water (20 mL) was added and thelayers were separated. The aqueous phase was extracted with DCM (4×30mL) and the combined organic layers were dried over magnesium sulfate,filtered, and concentrated in vacuo. The resulting residue was purifiedby flash column chromatography on silica gel (0%→20% EtOAc/DCM) toafford methyl 2-choro-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate(G1) as yellow solid.

The following intermediate compounds, as shown in Table 11, weresynthesized in analogous fashion to intermediate G1.

TABLE 11 Intermediate G Indole Pyrimidine

Example H13-(4-chloro-1,3,5-triazin-2-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-1H-indole

3-(4-chloro-1,3,5-triazin-2-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-1H-indole(D4) (374 mg, 1.2 mmol) was suspended in DMF (2.2 mL) and cooled to 0°C. Sodium hydride (62 mg, 1.55 mmol) was added and the resulting mixturewas warmed to rt and stirred for 15 min. The mixture was then treatedwith iodomethane (97 uL, 1.55 mmol, 1.3 equiv) and stirred at rt for 30min. Tert-butanol (1 mL) was added, and the resulting mixture wasdiluted with EtOAc (20 mL) and water (15 mL). The layers were separatedand the aqueous phase was extracted with EtOAc (3×10 mL). The combinedorganic layers were washed with brine (15 mL), dried over sodiumsulfate, filtered, and concentrated in vacuo. The resulting residue waspurified by flash column chromatography on silica gel (0%→20%EtOAc/heptane) to afford3-(4-chloro-1,3,5-triazin-2-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-1H-indole(H1) as a white powder.

The following intermediate compounds, as shown in Table 12, wereprepared in analogous fashion to intermediate H1.

TABLE 12 Intermediate H Indole

Intermediate H10 isopropyl4-(1-acetyl-1H-indol-3-yl)-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carboxylate

To a solution of isopropyl2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-4-(1H-indol-3-yl)pyrimidine-5-carboxylate(M44) (200 mg, 0.36 mmol) in DCE (5 mL), was added acetic anhydride (40mg, 0.4 mmol), followed by trimethylamine (0.055 mL, 0.4 mmol). Theresulting mixture was stirred at rt overnight. Subsequently, saturatedaqueous potassium carbonate was added, and the resulting mixture wasextracted with DCM. The combined organic layers were dried overmagnesium sulfate, filtered, and concentrated in vacuo. The resultingresidue was purified by flash column chromatography on silica gel (0→20%MeOH/DCM) to afford isopropyl4-(1-acetyl-1H-indol-3-yl)-2-((4-((2-(dimethyl)amino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidine-5-carboxylate(H10) as a red solid.

Intermediate 114-(2-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3,5-triazin-2-amine

A mixture of3-(4-chloro-1,3,5-triazin-2-yl)-2-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-1H-indolePGP-47 (H1) (263 mg, 0.80 mmol), 4-fluoro-2-methoxy-5-nitroaniline (A2)(150 mg, 0.80 mmol) and potassium carbonate (334 mg, 2.40 mmol) in MeCN(2.7 mL) was stirred overnight at 80° C. The mixture was cooled to rt,then filtered through a pad of Celite, which was rinsed with EtOAc. Thefiltrate was concentrated in vacuo to afford4-(2-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3,5-triazin-2-amine(11).

The following intermediate compounds, as shown in Table 13, wereprepared in analogous fashion to intermediate 11.

TABLE 13 Intermediate I Heteroaryl chloride Aniline

Intermediate J1N1-(2-(dimethylamino)ethyl)-N4-(5-ethyl-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)-5-methoxy-N1-methyl-2-nitrobenzene-1,4-diamine

A mixture of 3-(2-chloro-5-ethylpyrimidin-4-yl)pyrazolo[1,5-a]pyridine(F1) (61 mg, 0.24 mmol),N1-(2-(dimethylamino)ethyl)-5-methoxy-NM-methyl-2-nitrobenzene-1,4-diamine(A3) (53 mg, 0.20 mmol), tris(dibenzylideneacetone)dipalladium(0) (18mg, 0.02 mmol), Xantphos (23 mg, 0.04 mmol), and cesium carbonate (77mg, 0.24 mmol) in dioxane (1 mL) was stirred at 100° C. overnight. Uponcooling, the mixture was concentrated in vacuo. The resulting residuewas purified by flash column chromatography on silica gel (0%→15%MeOH/DCM) to affordN1-(2-(dimethylamino)-ethyl)-N4-(5-ethyl-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)-5-methoxy-N1-methyl-2-nitrobenzene-1,4-diamine(J1) as a red solid.

The following intermediate compounds, as shown in Table 14, weresynthesized in analogous fashion to intermediate J1.

TABLE 14 Intermediate J Chloropyrimidine Aniline

Intermediate K15-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1,6,7,8-tetrahydrocyclopenta[g]indol-3-yl)pyrimidin-2-amine

A mixture of intermediate3-(2,5-dichloropyridin-4-yl)-1-methyl-1,6,7,8-tetrahydrocyclopenta[g]indole(H6) (1.43 g, 4.5 mmol), 4-fluoro-2-methoxy-5-nitroaniline (A4) (1.0 g,5.4 mmol) and pTSA (3.42 g, 18 mmol) in dioxane (10 mL) was heated at100° C. for 48 h. Upon cooling, the mixture was concentrated in vacuoand the resulting residue was purified by flash column chromatography onsilica gel (5% MeOH/DCM) to afford5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1,6,7,8-tetrahydrocyclopenta[g]indol-3-yl)pyrimidin-2-amine(K1) as a brown residue.

The following intermediate compounds, as shown in Table 15, weresynthesized in analogous fashion to intermediate K1.

TABLE 15 Intermediate K Chloropyrimidine Aniline

Intermediate L1N-(2-chlor-4-(1-methyl-1H-indol-3-yl)pyrimidin-5-yl)isobutyramide

2-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-5-amine (G12) (150 mg, 0.58mmol) was suspended in DCM (5.8 mL) and treated with isobutyryl chloride(67 uL, 0.64 mmol) and triethylamine (161 uL, 1.16 mmol). The mixturewas stirred at rt for 1 h before adding water (5 mL). The layers wereseparated, and the aqueous layer was extracted with DCM (3×5 mL). Thecombined organic layers were dried over magnesium sulfate, filtered, andconcentrated in vacuo to giveN-(2-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-5-yl)isobutyramide (L1)as a pink solid.

Intermediate L2N-(2-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-5-yl)-N-methylisobutyramide

A solution ofN-(2-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-5-yl)isobutyramide (L1)(166 mg, 0.50 mmol, 1.0 equiv) in MeCN (2.0 mL) was treated with cesiumcarbonate (329 mg, 1.0 mmol, 2.0 equiv), and then iodomethane (41 uL,0.65 mmol, 1.3 equiv). The mixture was stirred for 15 h at rt.Subsequently, the mixture was diluted with DCM (10 mL) and filteredthrough Celite with additional DCM. The filtrate was then concentratedin vacuo. The resulting residue was purified by flash columnchromatography on silica gel (0%→75% EtOAc in heptane) to affordN-(2-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-5-yl)-N-methylisobutyramide(L2) as a red solid.

Intermediates L3 & L4N-(2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidin-5-yl)pivalamideN-(2-((2,4-dimethoxy-5-nitrophenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidin-5-yl)pivalamide

N2-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidine-2,5-diamine(17) (150 mg, 0.37 mmol) was suspended in DCM (1.8 mL) and treated withtrimethylacetyl chloride (50 uL, 0.40 mmol) and triethylamine (102 uL,0.74 mmol). The mixture was stirred at rt for 1 h. MeOH (1 mL) andpotassium carbonate (102 mg, 0.74 mmol) were added to the mixture andstirred at rt for an additional 30 min. The mixture was concentrated invacuo and purified by flash column chromatography on silica gel (0%→80%EtOAc in heptane) to affordN-(2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidin-5-yl)pivalamide(L3) andN-(2-((2,4-dimethoxy-5-nitrophenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidin-5-yl)pivalamide(L4).

Intermediate L5

To a solution of2-(3-(5-ethyl-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1H-indol-1-yl)aceticacid (K26) (0.34 g, 0.73 mmol) in DMF (3.6 mL) was added1-hydroxybenzotriazole hydrate (0.33 g, 2.19 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.42 g,2.19 mmol), ammonium chloride (0.39 g, 7.30 mmol), and thendiisopropylethylamine (0.64 ml, 3.65 mmol). The resulting mixture wasstirred overnight at rt. Subsequently, brine (50 mL) was added to themixture, and the precipitates were collected by vacuum filtration. Thecollected solids were washed with water (100 mL), and then dried invacuo at 60° C. to afford2-(3-(3-ethyl-6-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyridin-2-yl)-1H-indol-1-yl)acetamide(L5) as a brown solid.

The following compounds in Table 16 were prepared in analogous fashionto Intermediate L5.

TABLE 16 Compound Acid Amine

NH₄Cl

H₂NMe

Intermediate L83-(2-((4-((2-(dimethylamino)ethyl)(methy)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-2-carboxylicacid

To a mixture of methyl3-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-2-carboxylate(M50) (2.5 g, 4.7 mmol) in MeOH (10 mL) was added aqueous sodiumhydroxide (7 mL, 2 N), and the resulting mixture was stirred at 70° C.for 1 h. Upon cooling, HCl (1 N) was added to the mixture until the pHwas approximately 5. Subsequently, the mixture was concentrated invacuo, and the resulting residue was diluted with MeOH and filtered. Thefiltrate was concentrated in vacuo to afford3-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-2-carboxylicacid (L8) as a red solid.

Intermediate L93(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-2-carboxamide

To a solution of3-(2-((4-((2-(dimethylamino)ethyl)(methy)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-2-carboxylicacid (L8) (100 mg, 0.19 mmol) in DMF (3 mL), was added HOBt (39 mg, 0.29mmol) and EDCI (56 mg, 0.29 mmol). The resulting solution was stirred atrt for 20 min before ammonia in dioxane (0.95 mL, 0.4 M in THF) wasadded, followed by the addition of TEA (0.079 mL, 0.57 mmol).Subsequently, the mixture was stirred at rt for 1 h. The mixture wasthen diluted with water and extracted with EtOAc, and the combinedorganic layers were dried over magnesium sulfate, filtered, andconcentrated in vacuo to afford3-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-2-carboxamide(L9) as a red solid.

The following intermediate compounds, as shown in Table 17, weresynthesized in analogous fashion to Intermediate L9.

TABLE 17 Intermediate L Acid Amine

Intermediate M1N1-(4-(2-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)-N4-(2-(dimethylamino)ethyl)-2-methoxy-N4-methyl-5-nitrobenzene-1,4-diamine

A mixture of4-(2-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-1H-indol-3-yl)-N-(4-fluoro-2-methoxy-5-nitrophenyl)-1,3,5-triazin-2-amine(11) (383 mg, 0.80 mmol) and N,N,N′-trimethylethylenediamine (114 uL,0.88 mmol) in MeCN (1.1 mL) was treated with potassium carbonate (334mg, 2.40 mmol). The resulting mixture was stirred for 90 min at 80° C.Upon cooling, the mixture was filtered through a pad of Celite andrinsed with EtOAc. The filtrate was concentrated in vacuo and theresulting residue was purified by flash column chromatography on silicagel (0%→5% 1.4 N ammonia in MeOH/DCM) to affordN1-(4-(2-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)-N4-(2-(dimethylamino)ethyl)-2-methoxy-N4-methyl-5-nitrobenzene-1,4-diamine(M1) as a red oil.

The following intermediate compounds, as shown in Table 18, weresynthesized in analogous fashion to intermediate M1.

TABLE 18 Intermediate M Aryl fluroide Amine

Intermediate N1(R)-5-chloro-N-(4-((1-(dimethylamino)-3-ethoxypropan-2-yl)oxy)-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

To a solution of (R)-1-(dimethylamino)-3-ethoxypropan-2-ol (A4) (131 mg,0.9 mmol) in DMF (5 mL) was added sodium hydride (72 mg, 1.8 mmol, 60%dispersion in oil) at rt. After stirring at rt for 10 min,5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine(K15) (190 mg, 0.45 mmol) was added, the mixture was stirred at rt for 4h. Subsequently, the mixture was concentrated in vacuo, and theresulting residue was dissolved in DCM and washed with saturatedammonium chloride. The aqueous phase was extracted with DCM (2×20 mL)and the organic layers were combined, dried over sodium sulfate,filtered and concentrated in vacuo. The resulting residue was purifiedby flash column chromatography on silica gel (5% MeOH/DCM) to afford(R)-5-chloro-N-(4-((1-(dimethylamino)-3-ethoxypropan-2-yl)oxy)-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine(N1).

The following intermediate compounds, as shown in Table 19, weresynthesized in analogous fashion to intermediate N1.

TABLE 19 Intermediate N Aryl fluroide Alcohol

Intermediate O1 5-chloro-N-(4-(3-(dimethylamino)prop-1-yn-1-yl)-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine

To a mixture ofN-(4-bromo-2-methoxy-5-nitrophenyl)-5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine(K2) (110 mg, 0.22 mmol), bis(triphenylphosphine)-palladium(II)dichloride (8 mg, 0.011 mmol), and copper(I) iodide (4 mg, 0.022 mmol)in DMF (3 mL) was added N,N-diisopropylethylamine (0.06 mL, 0.36 mmol)and N,N-dimethylpropargylamine (30 mg, 0.060 mL, 0.36 mmol). Theresulting mixture was heated at 90° C. overnight. Upon cooling, themixture was concentrated in vacuo and the resulting residue was purifiedby flash column chromatography on silica gel (5% MeOH/DCM) to afford5-chloro-N-(4-(3-(dimethylamino)prop-1-yn-1-yl)-2-methoxy-5-nitrophenyl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine(01) as a brown residue.

The following intermediate compounds, as shown in Table 20, weresynthesized in analogous fashion to intermediate O1.

TABLE 20 Intermediate O Aryl bromide Alkyne

Intermediate P1N1-(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)-N4-(2-((2-fluoroethyl)methyl)amino)ethyl)-2-methoxy-N4-methyl-5-nitrobenzene-1,4-diamine

To a solution ofN1-(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)-2-methoxy-N4-methyl-N4-(2-(methylamino)ethyl)-5-nitrobenzene-1,4-diamine(M19) (0.2 g, 0.42 mmol) in DMF (2 mL) was added 1-bromo-2-fluoroethane(0.1 g, 0.79 mmol) and sodium bicarbonate (87 mg, 0.83 mmol) at rt. Theresulting mixture was heated at 80° C. overnight. Upon cooling, themixture was concentrated in vacuo and the resulting residue was purifiedby flash column chromatography on silica gel to affordN1-(5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)-N4-(2-((2-fluoroethyl)(methyl)-amino)ethyl)-2-methoxy-N4-methyl-5-nitrobenzene-1,4-diamine(P1).

The following compounds in Table 21 were prepared in analogous fashionto Intermediate P1.

TABLE 21 Compound Hereocycle Halide

Intermediate Q1 ethyl2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate

To a mixture of methyl2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate(M4) (110 mg, 0.21 mmol) in EtOH (3.0 mL) was added sodium hydride (10mg, 0.26 mmol, 60% dispersion in mineral oil). The resulting mixture wasthen heated to reflux for 5 min. Upon cooling, the mixture was filteredand rinsed with EtOH to afford ethyl2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate(Q1) as a red solid.

The following intermediate compounds, as shown in Table 22, weresynthesized in analogous fashion to intermediate Q1.

TABLE 22 Intermediate Q Ester Alcohol

iPrOH

iPrOH

iPrOH

iPrOH

iPrOH

iPrOH

iPrOH

iPrOH

iPrOH

iPrOH

iPrOH

iPrOH

Intermediate Q23(3-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indol-2-yl)methanol

To a mixture of methyl3-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-2-carboxylate(M50) (533 mg, mmol) in DCM (20 mL), at −78° C., was added DIBAL (1 M inDCM, 3 mL) dropwise. The resulting mixture was stirred for 1 h beforeadding saturated aqueous ammonium chloride and extracting with DCM. Thecombined organic layers were dried over magnesium sulfate, filtered, andconcentrated in vacuo. The resulting residue was purified by flashcolumn chromatography (25% MeOH/DCM) to afford(3-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indol-2-yl)methanol(Q23) as a red solid.

Intermediate Q243-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-2-carbaldehyde

To a stirred solution of DMSO (77 mg, 0.99 mmol) in DCM (3 mL), at −78°C., was added oxalyl chloride (2 M in DCM, 0.25 mL) dropwise, and themixture was stirred for 30 min. Subsequently, a mixture of(3-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indol-2-yl)methanol(170 mg, 0.33 mmol) in DCM (2 mL) was added, and the mixture was stirredfor 1 h. To that mixture was added TEA (100 mg, 0.99 mmol) beforewarming to rt. Saturated sodium bicarbonate was added to the mixture,which was then extracted with DCM. The combined organic layers weredried over magnesium sulfate, filtered, and concentrated in vacuo. Theresulting residue was purified by flash column chromatography on silicagel (25% MeOH/DCM) to afford3-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-2-carbaldehyde(Q24) as a red solid.

Intermediate Q25 methyl3-(((3-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indol-2-yl)methyl)amino)propanoate

To methyl 3-aminopropanoate hydrochloride (58 mg, 0.42 mmol) in, DCE (5mL), was added TEA (42 mg, 0.42 mmol), and the mixture was stirred at70° C. for 20 minutes. Upon cooling,3-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indole-2-carbaldehyde(Q24) (140 mg, 0.28 mmol) was added, and the mixture was stirred at rtfor 1 h. Subsequently, saturated aqueous sodium bicarbonate was added tothe mixture, which was then extracted with DCM. The combined organiclayers were dried over magnesium sulfate, filtered, and concentratedunder reduced pressure. The resulting residue was purified by flashcolumn chromatography on silica gel (20% MeOH/DCM) to afford methyl3-(((3-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indol-2-yl)methyl)amino)propanoate(Q25) as a red solid.

Intermediate Q261-((3-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indol-2-yl)methyl)azetidin-2-one

To methyl3-(((3-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indol-2-yl)methyl)amino)propanoate(Q25) (159 mg, 0.27 mmol) in DCE (3 mL), at −78° C., was addedtrimethylaluminum (2 M in PhMe, 0.13 mL). Subsequently, the mixture washeated to 90° C., and stirred for 3 h. Upon cooling, saturated aqueoussodium bicarbonate was added, and the resulting mixture was extractedwith DCM. The combined organic layers were dried over magnesium sulfate,filtered, and concentrated in vacuo. The resulting residue was purifiedby flash chromatography (25% MeOH/DCM) to afford1-((3-(2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)-1-methyl-1H-indol-2-yl)methyl)azetidin-2-one(Q26) as a red solid.

Intermediate R1N1-(2-(dimethylamino)ethyl)-N4-(5-ethyl-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)-5-methoxy-N1-methylbenzene-1,2,4-triamine

A solution ofN1-(2-(dimethylamino)ethyl)-N4-(5-ethyl-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)-5-methoxy-N1-methyl-2-nitrobenzene-1,4-diamine(J1) (69 mg, 0.14 mmol) in acetone (1.4 mL) was treated with zinc powder(37 mg, 0.56 mmol) and saturated aqueous ammonium chloride solution (0.2mL, 1.4 mmol). The resulting mixture was stirred at rt for 30 min. Themixture was then filtered through a pad of Celite, and the collectedsolids were rinsed with MeOH. The filtrate was concentrated in vacuo toaffordN1-(2-(dimethylamino)-ethyl)-N4-(5-ethyl-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)-5-methoxy-N1-methylbenzene-1,2,4-triamine(R₁).

The following intermediate compounds, as shown in Table 23, weresynthesized in analogous fashion to intermediate R1.

TABLE 23 Intermediate R Nitro compound

Intermediate S1N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methy-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-1,3,5-triazin-2-yl)benzene-1,2,4-triamine

To a microwave vial was addedN4-(4-(2-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-1H-indol-3-yl)-1,3,5-triazin-2-yl)-N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methylbenzene-1,2,4-triamine(R₂) (79 mg, 0.15 mmol), MeOH (1.0 mL), palladium on carbon (10 wt-%, 85mg, 0.08 mmol), and ammonium formate (93 mg, 1.5 mmol). The resultingmixture was microwaved for 60 min at 80° C. The mixture was thenfiltered through a Celite pad and rinsed with 20% MeOH in DCM. Thefiltrate was concentrated in vacuo, and the resulting residue waspurified by flash column chromatography on silica gel (0%→10% MeOH/DCM)to affordN1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methyl-N4-(4-(1-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-1,3,5-triazin-2-yl)benzene-1,2,4-triamine(S1) as a red viscous oil.

The following intermediate compounds, as shown in Table 24, weresynthesized in analogous fashion to intermediate S1.

TABLE 24 Intermediate S Nitro compound

Intermediate T1 Isopropyl2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indazol-3-yl)pyrimidine-5-carboxylate

To a solution of isopropyl2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-4-(1-methyl-1H-indazol-3-yl)pyrimidine-5-carboxylate(M28) (70 mg, 0.12 mmol) in MeOH (1.2 mL) was added Pd/C (10 wt.-%, 13mg, 0.01 mmol), and the resulting mixture was stirred at rt under ahydrogen atmosphere for 1 h. Subsequently, the mixture was diluted withDCM (5 mL), and then filtered through a pad Celite, rinsing withadditional DCM (30 mL). The filtrate was concentrated in vacuo to affordisopropyl2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indazol-3-yl)pyrimidine-5-carboxylateas a yellow residue.

The following intermediate compounds, as shown in Table 25, weresynthesized in analogous fashion to intermediate R1.

TABLE 25 Intermediate T Nitro compound

Example 1N-(2-((2-(dimethylamino)ethyl)methyl)amino)-5-((5-ethyl-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

A solution ofN1-(2-(dimethylamino)ethyl)-N4-(5-ethyl-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)-5-methoxy-N¹-methylbenzene-1,2,4-triamine(R₁) (64 mg, 0.14 mmol) in DCM (1.4 mL) was treated with EDCI (54 mg,0.28 mmol), Hunig's base (73 uL, 0.42 mmol), and acrylic acid (19 uL,0.28 mmol). The mixture was concentrated in vacuo and the product waspurified by preparative TLC (5% MeOH/DCM) to affordN-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((5-ethyl-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide(Example 1) as an orange solid. ¹H NMR (CDCl₃): δ 10.01 (br. s., 1H),9.48 (s, 1H), 8.50 (dt, J=6.9, 1.1 Hz, 1H), 8.40 (m, 2H), 8.33 (s, 1H),7.41 (s, 1H), 7.21-7.25 (m, 1H), 6.83-6.89 (m, 1H), 6.78 (s, 1H),6.24-6.41 (m, 2H), 5.66 (dd, J=9.9, 1.7 Hz, 1H), 3.86 (s, 3H), 2.85-2.91(m, 2H), 2.81 (q, J=7.4 Hz, 2H), 2.70 (s, 3H), 2.27-2.31 (m, 3H), 2.25(s, 6H), 1.28 (t, J=7.5 Hz, 3H). ESI-MS m/z: 515.2 [M+H]⁺.

The following example compounds, as shown in Table 26, were synthesizedin analogous fashion to Example 1.

TABLE 26 Ex. Compound Amine compound 2

N-(5-((4-(2-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-1H-indol-3-yl)-1,3,5-triazin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4- methoxyphenyl)acrylamide ¹H NMR:(CDCl₃) δ 10.09 (br. s., 1H), 9.46 (br. s., 1H), 8.74-8.80 (m, 1H), 8.66(d, J = 7.9 Hz, 1H), 7.46 (br. s., 1H), 7.20-7.37 (m, 2H), 6.81 (s, 1H),6.41 (d, J = 16.8 Hz, 1H), 6.24-6.35 (m, 1H), 5.81 (br. s., 1H),5.62-5.70 (m, 1H), 4.40 (d, J = 2.3 Hz, 2H), 4.02 (br. s., 2H), 3.89 (s,3H), 3.75 (s, 3H), 2.82- 2.95 (m, 2H), 2.72 (s, 3H), 2.47 (br. s., 2H),2.24-2.34 (m, 8H) ESI-MS m/z: 583.5 [M + H]⁺ 3

N-(2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-2-phenyl-1H- indol-3-yl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide ¹H NMR: (CDCl₃) δ 10.04 (br. s., 1H), 9.34(br. s., 1H), 8.66 (d, J = 8.4 Hz, 1H), 8.59 (br. s., 1H), 7.37-7.48 (m,6H), 7.27-7.35 (m, 2H), 7.14 (s, 1H), 6.77 (s, 1H), 6.35-6.44 (m, 1H),6.23- 6.34 (m, 1H), 5.64-5.73 (m, 1H), 3.85 (s, 3H), 3.61 (s, 3H), 2.86(t, J = 5.5 Hz, 2H), 2.70 (s, 3H), 2.30 (obs. m., 2H), 2.26 (s, 6H)ESI-MS m/z: 577.3 [M + H]⁺ 4

N-(2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-2-(tetrahydro-2H-pyran-4-yl)-1H-indol-3-yl)-1,3,5-triazin-2-yl)amino)phenyl)acrylamide ¹H NMR: (TFA salt) (CDCl₃) δ 11.14(br. s., 1H), 9.04 (s, 1H), 8.86 (br. s., 1H), 8.59 (br. s., 1H), 8.39(d, J = 7.0 Hz, 1H), 7.30 (s, 3H), 7.17 (br. s., 1H), 6.85 (dd, J =16.8, 10.3 Hz, 1H), 6.78 (s, 1H), 6.35 (d, J = 16.3 Hz, 1H), 5.70 (d, J= 10.9 Hz, 1H), 4.91 (br. s., 1H), 3.97 (obs. m, 2H), 3.93 (s, 3H), 3.84(s, 3H), 3.30-3.34 (m, 2H), 3.20-3.25 (m, 2H), 3.22 (br. s., 32), 2.85(s, 6H), 2.68 (s, 3H), 2.23 (br. s., 2H), 1.67 (d, J = 11.2 Hz, 2H)ESI-MS m/z: 585.3 [M + H]⁺ 5

N-(5-((4-(2-(3-chloro-4-(pyridin-2- ylmethoxy)phenyl)-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide ¹H NMR: (MeOH-d₄): δ 8.50-8.64 (m, 2H), 8.31(d, J = 7.9 Hz, 1H), 8.10 (d, J = 5.4 Hz, 1H), 7.95 (td, J = 7.7, 1.8Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.49-7.57 (m, 2H), 7.41-7.46 (m, 1H),7.37-7.41 (m, 1H), 7.32-7.35 (m, 1H), 7.29 (ddd, J = 8.3, 7.1, 1.2 Hz,1H), 7.18 (td, J = 7.6, 0.9 Hz, 1H), 6.95 (s, 1H), 6.38-6.52 (m, 3H),5.81-5.90 (m, 1H), 5.37 (s, 2H), 4.02 (s, 3H), 3.67 (s, 3H), 3.48 (br.s., 2H), 3.26 (br. s., 2H), 2.85 (br. s., 6H), 2.71 (s, 3H) ESI-MS m/z:717.3 [M + H]⁺ 6

N-(5-((4-(2-(5-chloropyridin-3-yl)-1- methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide ¹H NMR: (CDCl₃): δ 9.99-10.04 (m, 1H), 10.01(br. s., 1H), 9.45-9.48 (m, 1H), 9.45-9.48 (m, 1H), 9.46 (s, 1H), 8.65(d, J = 2.4 Hz, 1H), 8.56 (d, J = 1.8 Hz, 1H), 8.34 (d, J = 5.3 Hz, 1H),8.29 (d, J = 7.8 Hz, 1H), 7.82-7.86 (m, 1H), 7.42 (d, J = 8.4 Hz, 1H),6.79 (s, 1H), 6.50 (d, J = 5.3 Hz, 1H), 6.26-6.45 (m, 2H), 5.67 (dd, J =9.9, 1.8 Hz, 1H), 3.89 (s, 3H), 3.68 (s, 3H), 2.90 (t, J = 5.6 Hz, 2H),2.72 (s, 3H), 2.26-2.35 (m, 8H) ESI-MS m/z: 611.5 [M + H]⁺ 7

N-(2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-2-phenyl-1H- indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide 1H NMR: (CDCl₃): δ: 9.93 (br. s., 1H), 9.40(s, 1H), 8.28-8.55 (m, 1H), 7.88- 8.15 (m, 1H), 7.38-7.42 (m, 4H), 7.16-7.35 (m, 5H), 6.70 (s, 1H), 6.16-6.34 (m, 2H), 6.07 (d, J = 5.4 Hz, 1H),5.56 (dd, J = 9.7, 2.0 Hz, 1H), 3.79 (s, 3H), 3.52 (s, 3H), 2.80 (t, J =5.6 Hz, 2H), 2.61 (s, 3H), 2.15-2.27 (m, 9H) ESI-MS m/z: 576.3 [M + H]⁺8

methyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H- indol-3-yl)pyrimidine-5-carboxylate¹H NMR (CDCl₃) δ 10.19 (br. s., 1 H), 9.79 (s, 1 H), 8.92 (s, 1 H), 8.82(br. s., 1 H), 7.94 (s, 1 H), 7.53 (d, J = 12.42 Hz, 1 H), 7.36 (d, J =7.71 Hz, 1 H), 7.19- 7.31 (m, 2 H), 6.81 (s, 1 H), 6.44- 6.53 (m, 1 H),6.38 (d, J = 8.78 Hz, 1 H), 5.71-5.77 (m, 1 H), 3.98 (s, 3 H), 3.90 (s,3 H), 3.65 (s, 3 H), 2.90 (br. s., 2 H), 2.69-2.76 (m, 3 H), 2.28 (br.s., 8 H) ESI-MS m/z: 559.3 [M + H]⁺ 9

ethyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H- indol-3-yl)pyrimidine-5-carboxylate¹H NMR (CDCl₃) δ 10.16 (br. s., 1 H), 9.80 (s, 1 H), 8.93 (s, 1 H), 8.77(br. s., 1 H), 7.93 (s, 1 H), 7.54 (br. s., 1 H), 7.16-7.37 (m, 3 H),6.81 (s, 1 H), 6.44- 6.54 (m, 1 H), 6.40 (br. s., 1 H), 5.74 (d, J =11.92 Hz, 1 H), 4.07-4.19 (m, 2 H), 3.97 (s, 3 H), 3.88-3.92 (s, 3 H),2.92 (m, 2 H), 2.73 (s, 3 H), 2.30-2.56 (m, 8 H), 0.84-1.08 (m, 3 H)ESI-MS m/z: 573.3 [M + H]⁺ 10

isopropyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H- indol-3-yl)pyrimidine-5-carboxylate¹H NMR (CDCl₃) δ 10.15 (s, 1 H), 9.80 (s, 1 H), 8.91 (s, 1 H), 8.70 (br.s., 1 H), 7.91 (s, 1 H), 7.48-7.71 (m, 1 H), 7.15- 7.37 (m, 3 H), 6.81(s, 1 H), 6.49 (dd, J = 17.07, 1.88 Hz, 1 H), 6.36 (dd, J = 16.94, 10.04Hz, 1 H), 5.73 (dd, J = 10.04, 1.88 Hz, 1 H), 5.02 (dt, J = 12.45, 6.26Hz, 1 H), 4.00 (s, 3 H), 3.90 (s, 3 H), 2.86-2.93 (m, 2 H), 2.76 (s, 3H), 2.26-2.31 (m, 8 H), 1.05 (d, J = 6.15 Hz, 6 H) ESI-MS m/z: 586.3[M + H]⁺ 11

oxetan-3-yl 2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H- indol-3-yl)pyrimidine-5-carboxylate¹H NMR: (CDCl₃) δ 10.11 (s, 1 H), 9.72 (s, 1 H), 8.87 (br. s., 1 H),8.78 (br. s., 1 H), 7.89 (s, 1 H), 7.36 (br. s., 1 H), 7.19-7.20 (m, 1H), 7.14 (t, J = 7.16 Hz, 1 H), 7.02-7.09 (m, 1 H), 6.73 (s, 1 H), 6.41(dd, J = 16.64 Hz, 1 H), 6.28 (dd, J = 16.94, 10.04 Hz, 1 H), 5.65 (dd,J = 10.04, 1.88 Hz, 1 H), 5.44-5.52 (m, 1 H), 4.56 (t, J = 6.71 Hz, 2H), 4.21 (br. s., 2 H), 3.79-3.90 (m, 6 H), 2.77- 2.84 (m, 2 H), 2.63(s, 3 H), 2.10-2.29 (m, 9 H) ESI-MS m/z: 600.4 [M + H]⁺ 12

1-methylazetidin-3-yl 2-((5-acrylamido- 4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H- indol-3-yl)pyrimidine-5-carboxylate¹H NMR: (MeOH-d₄) δ 8.64 (br. s., 1 H), 8.33-8.37 (m, 1 H), 7.99-8.09(m, 1 H), 7.60 (s, 1 H), 7.37 (d, J = 8.28 Hz, 1 H), 7.15 (t, J = 7.19Hz, 1 H), 7.01-7.09 (m, 1 H), 6.87 (s, 1 H), 6.29-6.41 (m, 2 H),5.71-5.78 (m, 1 H), 3.88-3.92 (m, 3 H), 3.76-3.80 (m, 3 H), 3.35-3.55(m, 1 H), 3.24-3.33 (m, 2 H), 2.98-3.11 (m, 2 H), 2.95 (br. s., 2 H),2.56-2.66 (m, 6 H), 2.41 (br. s., 2 H), 2.30 (s, 3 H), 1.46-1.68 (m, 2H) ESI-MS m/z: 613.4 [M + H]⁺ 13

cyclopropyl methyl 2-((5-acrylamido-4- ((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate ¹H NMR: (CDCl₃) δ 10.12 (br. s., 1H), 9.80 (s, 1 H), 8.94 (s, 1 H), 8.76 (br. s., 1 H), 7.89-7.99 (m, 1H), 7.56 (d, J = 7.78 Hz, 1 H), 7.14-7.38 (m, 3 H), 6.81 (s, 1 H),6.37-6.57 (m, 2 H), 5.71- 5.77 (m, 1 H), 3.86-4.00 (m, 7 H), 2.93 (br.s., 2 H), 2.70-2.75 (m, 3 H), 2.32 (br. s., 8 H), 0.37 (d, J = 7.40 Hz,2 H) ESI-MS m/z: 598.4 [M + H]⁺ 14

cyclobutyl 2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H- indol-3-yl)pyrimidine-5-carboxylate¹H NMR: (CDCl₃) δ 9.80 (s, 1 H), 8.94 (s, 1 H), 8.76 (br. s., 1 H),7.89-7.99 (m, 1 H), 7.56 (d, J = 7.78 Hz, 1 H), 7.14- 7.38 (m, 3 H),6.81 (s, 1 H), 6.37- 6.57 (m, 1 H), 5.71-5.77 (m, 1 H), 4.95-5.05 (m,1H), 3.86-4.00 (m, 6 H), 2.93 (br. s., 2 H), 2.20-2.75 (m, 11 H),1.88-2.02 (m, 2 H), 1.78 (br. s., 1 H), 1.24-1.35 (m, 1 H) ESI-MS m/z:598.4 [M + H]⁺ 15

isopropyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1H-indol-1- yl)pyrimidine-5-carboxylate ¹H NMR(CDCl₃): δ 9.95 (br. s., 1H), 9.48 (s, 1H), 8.97 (br. s., 1H), 7.83 (s,2H), 7.32-7.57 (m, 2H), 7.07 (q, J = 7.0 Hz, 2H), 6.70 (s, 1H), 6.62 (d,J = 3.9 Hz, 1H), 6.40 (br. s., 2H), 5.53-5.74 (m, 1H), 4.75-4.91 (m,1H), 3.80 (s, 3H), 2.85 (br. s., 2H), 2.63 (s, 3H), 2.19-2.40 (m, 8H),0.84 (br. s., 6H) ESI-MS m/z: 572.3 [M + H]⁺ 16

methyl 2-((5-acrylamido-2-methoxy-4- (methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)amino)-4-(1- methyl-1H-indol-3-yl)pyrimidine-5-carboxylate ¹H NMR: (MeOH-d₄) δ 9.30 (br. s., 1 H), 8.78 (s, 1 H), 8.31(br. s., 1 H), 7.68 (d, J = 7.40 Hz, 1 H), 7.46 (d, J = 8.45 Hz, 1 H),7.23 (t, J = 7.22 Hz, 1 H), 7.10- 7.16 (m, 1 H), 7.01 (s, 1 H), 6.56(dd, J = 17.00, 10.10 Hz, 1 H), 6.41 (dd, J = 16.91 Hz, 1.63 Hz, 1 H),5.83 (dd, J = 10.10, 1.69 Hz, 1 H), 3.96 (s, 3 H), 3.94 (s, 3 H), 3.70(s, 3 H), 3.05-3.24 (m, 2 H), 2.92-2.87 (m, 1 H), 2.76 (s, 3 H),2.69-2.71 (m, 1 H), 2.50 (s, 3 H), 2.29-2.47 (m, 1 H), 1.96-2.20 (m, 1H), 1.73-1.92 (m, 2 H), 1.53-1.71 (m, 1 H) ESI-MS m/z: 584.4 [M + H]⁺ 17

isopropyl 2-((5-acrylamido-2-methoxy- 4-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)amino)-4-(1- methyl-1H-indol-3-yl)pyrimidine-5-carboxylate ¹H NMR: (MeOH-d₄) δ 9.33 (br. s., 1 H), 8.75 (s, 1 H), 8.29(br. s., 1 H), 7.67 (d, J = 7.78 Hz, 1 H), 7.47 (d, J = 8.16 Hz, 1 H),7.24 (t, J = 7.65 Hz, 1 H), 7.10- 7.16 (m, 1 H), 7.01 (s, 1 H),6.51-6.60 (m, 1 H), 6.45 (dd, J = 16.94 Hz, 1.76 Hz, 1 H), 5.84 (dd, J =10.04, 1.63 Hz, 3 H), 5.00-5.05 (m, 1 H), 3.96 (s, 3 H), 3.94 (s, 3 H),3.13-3.15 (m, 2 H), 2.92 (m, 1 H), 2.76 (s, 3 H), 2.68-2.81 (m, 1 H),2.51 (s, 3 H), 2.41- 2.58 (m, 1 H), 1.98-2.20 (m, 1 H), 1.73-1.92 (m, 2H), 1.50-1.72 (m, 1 H), 1.10 (s, 3 H), 1.08 (s, 3 H) ESI-MS m/z: 612.4[M + H]⁺ 18

N-(3-((5-chloro-4-(1-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)-1H-indol- 3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide ¹H NMR: (DMSO-d₆) δ 8.54 (s, 1H), 8.48 (d, 1H),8.14 (s, 1H), 7.79 (s, 2H), 7.15 (s,1H), 6.90 (d, 3H), 6.34 (d, 1H),6.08 (m, 1H), 5.69 (d, 1H), 4.21 (s, 2H), 3.91 (s, 6H), 2.90 (m, 9H),2.48 (s, 3H) ESI-MS m/z: 576 [M + H]⁺ 19

N-(3-((5-cyano-4-(6-(3- (dimethylamino)propoxy)-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-4- methoxyphenyl)acrylamide ¹H NMR:(DMSO-d₆) δ 10.10 (s, 1H), 9.40 (s, 1H), 8.68 (s, 1H), 8.39 (s, 1H),7.83 (s, 1H), 7.65 (d, J = 9.2, 1H), 7.10 (m, 2H), 6.63 (s, 1H), 6.41(dd, J = 10, 16.8, 1H), 6.22 (d, J = 16.8, 1H), 5.72 (d, J = 10, 1H),4.09 (s, 2H), 3.87 (s, 3H), 3.74 (s, 3H), 3.10 (m, 2H), 2.74 (m, 6H)2.10 (s, 2H) ESI-MS m/z: 526 [M + H]⁺ 20

N-(3-((5-cyano-4-(1-methyl-6-(2- (pyrrolidin-1-yl)ethoxy)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4- methoxyphenyl)acrylamide ¹H NMR: (DMSO-d₆) δ10.16 (s, 1H), 10.13 (br s, 1H), 9.46 (s, 1H), 8.70 (s, 1H), 8.42 (s,1H), 7.82 (s, 1H), 7.67 (s, 1H), 7.12 (m, 2H), 6.69 (br, 1H), 6.42 (dd,J = 10, 16.8, 1H), 6.22 (dd, J = 2.0, 16.8, 1H), 6.22 (dd, J = 2.0,10.0, 1H), 4.36 (s, 2H), 3.61 (m, 4H), 3.12 (m, 2H), 1.96 (m, 4H) ESI-MSm/z: 538 [M + H]⁺ 21

N-(3-((5-cyano-4-(1-methyl-6-((1- methylpyrrolidin-2-yl)methoxy)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4- methoxyphenyl)acrylamide ¹H NMR:(DMSO-d₆) δ 10.08 (s, 1H), 9.37 (s, 1H), 8.68 (s, 1H), 8.38 (s, 1H),7.86 (s, 1H), 7.62 (d, 1H), 7.12 (m, 2H), 6.60 (s, 1H), 6.43 (m, 1H),6.23 (d, 1H), 5.71 (d, 1H), 4.03 (s, 1H), 3.88 (s, 4H), 3.75 (s, 3H),2.99 (m, 1H), 2.50 (m, 1H), 2.39 (s, 3H), 2.22 (m, 1H), 2.01 (m, 1H),1.69 (m, 3H) ESI-MS m/z: 538 [M + H]⁺ 22

N-(3-((5-chloro-4-(6-(2-(pyrrolidin-1-yl)ethoxy)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide ¹H NMR: (DMSO-d₆) δ 11.65 (s, 1H),10.01 (s, 1H), 8.43-8.37 (m, 2H), 8.17 (d, 1H), 8.00 (d, 1H), 7.55 (dd,1H), 7.06 (d, 1H), 6.93 (d, 1H), 6.60 (dd, 1H), 6.40 (dd, 1H), 6.21 (dd,1H), 5.69 (dd, 1H), 4.06 (t, 2H), 3.78 (s, 3H), 2.80 (t, 2H), 2.52 (s,4H), 1.71-1.67 (m, 4H) ESI-MS m/z: 532.5 [M + H]⁺ 23

N-(3-((5-cyano-4-(1-methyl-6-(2-(1-methylpyrrolidin-2-yl)ethoxy)-1H-indol- 3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide ¹H NMR: (DMSO-d₆) δ 10.12 (s, 1H), 9.39 (s,1H), 8.68 (s, 1H), 8.39 (s, 1H), 7.84 (s, 1H), 7.64 (d, J = 8.4, 1H),7.10 (m, 2H), 6.63 (s, 1H), 6.42 (dd, J = 10, 16.8, 1H), 6.22 (d, J =16.8, 1H), 5.72 (d, J = 10, 1H), 4.12 (m, 2H), 3.87 (s, 3H), 3.74 (s,3H), 2.74 (m, 4H), 2.33 (m, 2H), 1.93 (m, 4H), 1.73 (m, 2H) ESI-MS m/z:552 [M + H]⁺ 24

N-(2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3- yl)pyrimidin-2-yl)amino)phenyl)acrylamide ¹H NMR: (MeOH-d₄) δ 9.42 (s, 1 H), 8.61 (s, 1H), 8.27 (d, J = 5.27 Hz, 1 H), 8.15 (d, J = 7.72 Hz, 1 H), 7.44 (d, J =7.91 Hz, 1 H), 7.18-7.27 (m, 3 H), 6.97 (s, 1 H), 6.60 (dd, J = 16.94,10.16 Hz, 1 H), 6.40 (d, J = 16.94 Hz, 1 H), 5.80 (d, J = 10.35 Hz, 1H), 3.95 (s, 3 H), 3.91 (s, 3 H), 3.04 (t, J = 5.74 Hz, 2 H), 2.70 (s, 3H), 2.43 (t, J = 5.65 Hz, 2 H), 2.29 (s, 6 H) ESI-MS m/z: 501.2 [M + H]⁺25

N-(5-((5-chloro-4-(pyrazolo[1,5- a]pyridin-3-yl)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)azetidin-1-yl)-4- methoxyphenyl)acrylamide ¹H NMR:(DMSO-d₆) δ 9.28 (s, 1H), 8.93 (s, 1H), 8.82 (d, 1H), 8.50 (s, 1H), 8.35(s, 2H), 7.41-7.35 (m, 1H), 7.11- 7.10 (m, 1H), 6.46-6.42 (m, 1H), 6.25(s, 1H), 6.16 (dd, 1H), 5.68-5.65 (m, 1H), 3.98 (t, 2H), 3.76 (s, 3H),3.58 (t, 2H), 3.09-3.08 (m, 1H), 2.09 (s, 6H) ESI-MS m/z: 519.2 [M + H]⁺26

N-(5-((5-chloro-4-(pyrazolo[1,5- a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methylpiperazin-1- yl)phenyl)acrylamide ¹H NMR: (DMSO-d₆) δ9.00 (s, 1H), 8.95 (s, 1H), 8.82 (d, 1H), 8.67 (s, 1H), 8.39-8.33 (m,2H), 8.11 (s, 1H), 7.34 (t, 1H), 7.12 (t, 1H), 6.89 (s, 1H), 6.64- 6.57(m, 1H), 6.16 (d, 1H), 5.70 (d, 1H), 3.77 (s, 3H), 2.90 (s, 4H), 2.56(s, 4H), 2.27 (s, 3H) ESI-MS m/z: 519.4 [M + H]⁺ 27

N-(5-((5-chloro-4-(pyrazolo[1,5- a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-(4- methylpiperazin-1-yl)ethyl)amino)phenyl)acrylamide ¹H NMR: (DMSO-d₆) δ 9.31 (s, 1H), 8.94(s, 1H), 8.82 (d, 1H), 8.68 (s, 1H), 8.38 (m, 2H), 8.23 (s, 1H), 7.31(m, 1H), 7.09 (m, 1H), 6.99 (s, 1H), 6.59 (m, 1H), 6.17 (d, 1H), 5.71(d, 1H), 3.77 (s, 3H), 3.00 (m, 2H), 2.70 (m, 3H), 2.35 (m, 10H), 2.13(s, 3H) ESI-MS m/z: 576.4 [M + H]⁺ 28

isobutyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H- indol-3-yl)pyrimidine-5-carboxylate¹H NMR: (CDCl₃) δ 9.74 (s, 1 H), 9.23 (br. s., 1 H), 8.83 (s, 1 H), 8.58(br. s., 1 H), 7.81 (s, 1 H), 7.45 (br. s., 1 H), 7.05- 7.27 (m, 3 H),6.76 (br. s., 1 H), 6.63 (s, 1 H), 6.42 (dd, J = 16.81, 1.88 Hz, 1 H),5.64-5.70 (m, 1 H), 3.84 (s, 3 H), 3.80 (s, 3 H), 3.74 (d, J = 6.53 Hz,2 H), 3.06 (br. s., 2 H), 2.88 (br. s., 1 H), 2.56- 2.73 (br. s., 9 H),1.39-1.72 (m, 2 H), 0.53 (d, J = 6.65 Hz, 6 H) ESI-MS m/z: 600.4 [M +H]⁺ 29

sec-butyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H- indol-3-yl)pyrimidine-5-carboxylate¹H NMR: (CDCl₃) δ 9.72 (s, 1 H), 8.73- 8.90 (m, 1 H), 8.55 (br. s., 1H), 7.81 (s, 1 H), 7.51 (br. s., 1 H), 7.03-7.29 (m, 3 H), 6.59-6.73 (m,1 H), 6.53 (br. s., 1 H), 6.38-6.48 (m, 1 H), 5.62- 5.69 (m, 1 H), 4.80(s, 3 H), 4.85 (s, 3 H), 2.93 (br. s., 2 H), 2.66 (s, 3 H), 2.30-2.58(br. s., 8 H), 1.23-1.42 (m, 2 H), 0.99 (d, J = 6.15 Hz, 3 H), 0.62-0.79(m, 3 H) ESI-MS m/z: 600.4 [M + H]⁺ 30

isopropyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1H-indol-3- yl)pyrimidine-5-carboxylate ¹H NMR:(CDCl₃) δ 10.11 (br. s., 1 H), 9.63 (s, 1 H), 9.24 (br. s., 1 H), 8.84(s, 1 H), 8.23 (br. s., 1 H), 7.83 (s, 1 H), 7.61 (br. s., 1 H),7.20-7.27 (m, 1 H), 6.94-7.10 (m, 2 H), 6.70 (s, 1 H), 6.15- 6.47 (m, 2H), 5.61 (d, J = 11.54 Hz, 1 H), 4.91 (dt, J = 12.49, 6.18 Hz, 1 H),3.78 (s, 3 H), 2.80 (t, J = 5.46 Hz, 2 H), 2.62 (s, 3 H), 2.17-2.29 (m,8 H), 0.96 (d, J = 5.90 Hz, 6 H) ESI-MS m/z: 572.5 [M + H]⁺ 31

isopropyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(7-methoxy- 1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate ¹H NMR: (CDCl₃) δ 10.14 (br. s., 1H), 9.76 (s, 1H), 8.86 (s,1H), 8.48 (br. s., 1H), 7.88 (s, 1H), 7.11 (br. s., 1H), 6.97 (t, J =7.9 Hz, 1H), 6.78 (s, 1H), 6.58 (d, J = 7.8 Hz, 1H), 6.46 (dd, J = 16.9,1.9 Hz, 1H), 6.28-6.40 (m, 1H), 5.65- 5.73 (m, 1H), 4.93-5.04 (m, 1H),4.18 (s, 3H), 3.90 (s, 3H), 3.86 (s, 3H), 2.76- 2.95 (m, 2H), 2.69 (s,3H), 2.21-2.30 (obs. m., 2H), 2.25 (s, 6H), 1.04 (d, J = 6.0 Hz, 6H)ESI-MS m/z: δ 616.6 [M + H]⁺ 32

isopropyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidine-5-carboxylate ¹H NMR: (CDCl₃) δ 10.08 (br. s.,1H), 9.54 (s, 1H), 8.98 (s, 1H), 8.52 (s, 1H), 8.49 (d, J = 6.9 Hz, 1H),8.14 (d, J = 8.9 Hz, 1H), 7.21-7.25 (m, 1H), 6.80- 6.85 (m, 1H), 6.80(s, 1H), 6.43 (dd, J = 16.9, 1.6 Hz, 1H), 6.24-6.35 (m, 1H), 5.69 (dd, J= 10.1, 1.6 Hz, 1H), 5.12- 5.22 (m, 1H), 3.87 (s, 3H), 2.81-2.92 (m,2H), 2.71 (m, 3H), 2.28-2.32 (m, 2H), 2.26 (s, 6H), 1.26 (d, J = 6.4 Hz,6H) ESI-MS m/z: 573.5 [M + H]⁺ 33

N-(5-((5-chloro-4-(pyrazolo[1,5- a]pyridin-3-yl)pyrimidin-2-yl)amino)-2-((2-((2- fluoroethyl)(methyl)amino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide ¹H NMR: (CDCl₃) δ 9.31-9.44 (m, 2H),8.87 (s, 1H), 8.43-8.51 (m, 2H), 8.38 (s, 1H), 7.37 (s, 1H), 7.19-7.21(m, 1H), 6.82 (td, J = 6.8, 1.0 Hz, 1H), 6.73 (s, 1H), 6.19-6.37 (m,2H), 5.60 (dd, J = 9.1, 2.2 Hz, 1H), 4.39-4.59 (m, 2H), 3.81 (s, 3H),2.85 (t, J = 5.7 Hz, 2H), 2.74 (t, J = 4.8 Hz, 1H), 2.62-2.69 (m, 4H),2.42 (t, J = 5.6 Hz, 2H), 2.26 (s, 3H) ESI-MS m/z: 553.2 [M + H]⁺ 34

isopropyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5- carboxylate ¹H NMR: (CDCl₃) δ10.06 (br. s., 1H), 9.70 (s, 1H), 8.53-9.06 (m, 2H), 8.25 (dd, J = 4.7,1.4 Hz, 1H), 7.84 (s, 2H), 7.01 (dd, J = 7.9, 4.6 Hz, 1H), 6.72 (s, 1H),6.16-6.54 (m, 2H), 5.54-5.75 (m, 1H), 4.96 (dt, J = 12.5, 6.2 Hz, 1H),3.96 (s, 3H), 3.81 (s, 3H), 2.82 (br. s., 2H), 2.63 (s, 3H), 2.22 (br.s., 8H), 1.02 (d, J = 6.0 Hz, 6H) ESI-MS m/z: 587.5 [M + H]⁺ 35

(S)-isopropyl 2-((5-acrylamido-2- methoxy-4-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)amino)-4-(1- methyl-1H-indol-3-yl)pyrimidine-5-carboxylate ¹H NMR: (CDCl₃) δ 12.17 (br. s., 1H), 9.91 (s,1H), 9.34(s,1H), 8.88 (s, 1H), 8.66 (s, 1H), 7.92 (s, 1H), 7.53 (d, J = 8.4 Hz,1H), 7.28-7.34 (m, 1H), 7.19- 7.23 (m,1H), 7.11-7.15 (m, 1H), 6.70 (s,1H), 6.52 (dd, J = 2, 16.8 Hz, 1H), 5.78 (dd, J = 2, 10.4 Hz, 1H),4.97-5.01 (m, 1H), 3.93 (s, 3H), 3.89 (s, 4H), 3.25-3.40 (m, 3H), 2.76(s, 4H), 2.57 (s, 3H), 2.15-2.21 (m, 2H), 2.04-2.05 (m, 1H), 1.84-1.85(m, 1H), 1.05 (d, J = 6.0 Hz, 3H), 0.97 (d, J = 4.8 Hz, 3H) ESI-MS m/z:613 [M + H]⁺ 36

(R)-isopropyl 2-((5-acrylamido-2- methoxy-4-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)amino)-4-(1- methyl-1H-indol-3-yl)pyrimidine-5-carboxylate ¹H NMR: (CDCl₃) δ 9.68-9.78 (m, 2 H), 8.81 (s, 1 H) 8.57(br. s., 1 H), 7.77 (s, 1 H), 7.50 (br. s., 1 H), 7.07-7.27 (m, 3 H),6.66 (s, 1 H), 6.37-6.44 (m, 1 H), 6.29 (dd, J = 16.94, 10.04 Hz, 1 H),5.65 (dd, J = 9.91, 1.88 Hz, 1 H), 4.92 (dt, J = 12.45, 6.26 Hz, 1 H),3.85 (s, 3 H), 3.80 (s, 3 H), 2.98-3.05 (m, 1 H), 2.82 (dd, J = 12.80,8.16 Hz, 1 H), 2.43-2.67 (m, 8 H), 2.25 (td, J = 9.32, 7.34 Hz, 1 H),1.88 (dq, J = 12.56, 8.78 Hz, 1 H), 1.57-1.69 (m, 2 H), 1.53 (s, 6 H),1.25- 1.45 (m, 1 H), 1.18 (s, 1 H), 0.96 (d, J = 15.18 Hz, 3 H), 0.94(d, J = 15.81 Hz, 3 H) ESI-MS m/z: 613 [M + H]⁺ 37

(R)-tetrahydrofuran-3-yl 2-((5- acrylamido-4-((2-(dimethylamino)ethyl)-(methyl)amino)-2- methoxyphenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine-5-carboxylate ¹H NMR: (CDCl₃) δ 10.10 (s, 1 H),9.68-9.73 (m, 1 H), 8.84 (s, 1 H), 7.86 (s, 1 H), 7.43 (d, J = 15.56 Hz,1 H), 7.05-7.30 (m, 3 H), 6.72 (s, 1 H), 6.34- 6.44 (m, 1 H), 6.16-6.34(m, 2 H), 5.61-5.68 (m, 1 H), 5.17-5.27 (m, 1 H), 4.91 (dd, J = 6.27 Hz,2 H), 3.74- 3.93 (m, 6 H), 3.52-3.66 (m, 2 H), 3.43 (d, J = 8.78 Hz, 1H), 3.31 (br. s., 1 H), 2.76-2.84 (m, 2 H), 2.63 (s, 3 H), 2.11-2.27 (m,8 H) ESI-MS m/z: 614 [M + H]⁺ 38

cyanomethyl 2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H- indol-3-yl)pyrimidine-5-carboxylate¹H NMR: (CDCl₃) δ 10.20 (br. s., 1 H), 9.78 (s, 1 H), 8.80-9.05 (m, 2H), 8.02 (s, 1 H), 7.34-7.45 (m, 2 H), 7.19- 7.32 (m, 2 H), 6.82 (s, 1H), 6.44 6.54 (m, 1 H), 6.32-6.44 (m, 1 H), 5.71-5.78 (m, 1 H), 4.68 (s,2 H), 3.89- 4.01 (m, 6 H), 2.98 (s, 1 H), 2.86- 2.95 (m, 2 H), 2.67-2.79(m, 3 H), 2.20-2.40 (m, 8 H) ESI-MS m/z: 583 [M + H]⁺ 39

N-(2-((2-(dimethylamino)ethyl)- (methyl)amino)-5-((5-isobutyramido-4-(1-methyl-1H-indol-3-yl)pyrimidin-2- yl)amino)-4-methoxyphenyl)-acrylamide ¹H NMR: (CDCl₃) δ 9.74 (s, 1H), 9.24 (s, 1H), 8.57 (br. s.,1H), 7.66 (s, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H),7.26-7.30 (m, 2H), 7.14- 7.21 (m, 1H), 6.70 (br. s., 1H), 6.44 (d, J =15.4 Hz, 1H), 5.70 (d, J = 12.0 Hz, 1H), 3.96 (s, 3H), 3.85 (s, 3H),2.98 (br. s., 2H), 2.68 (s, 3H), 2.25-2.62 (m, 9H), 1.15 (d, J = 6.8 Hz,6H) ESI-MS m/z: 585.5 [M + H]⁺ 40

N-(2-((2-(dimethylamino)ethyl)- (methyl)-amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-5-(N- methylisobutyramido)-pyrimidin-2-yl)amino)phenyl)acrylamide ¹H NMR: (CDCl₃) δ 10.10 (br. s., 1H), 9.51(s, 1H), 8.77 (d, J = 7.8 Hz, 1H), 8.29 (s, 1H), 7.62 (s, 1H), 7.46 (s,1H), 7.27-7.37 (m, 3H), 6.82 (s, 1H), 6.28- 6.42 (m, 2H), 5.64-5.69 (m,1H), 3.91 (s, 3H), 3.83 (s, 3H), 3.23 (s, 3H), 2.90 (t, J = 5.5 Hz, 2H),2.72 (s, 3H), 2.58 (m, 1H), 2.32-2.37 (m, 2H), 2.29 (s, 6H), 1.06 (d, J= 6.8 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H) ESI-MS m/z: 599.5 [M + H]⁺ 41

N-(2-((2-(dimethylamino)ethyl)- (methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-5- pivalamidopyrimidin-2-yl)amino)phenyl)acrylamide ¹H NMR: (CDCl₃) δ 9.74 (s, 1H), 9.27 (s, 1H),8.50 (s, 1H), 7.65 (s, 1H), 7.47- 7.54 (m, 2H), 7.39 (d, J = 8.2 Hz,1H), 7.24-7.28 (obs. m., 3H), 7.15-7.20 (m, 1H), 6.67 (s, 1H), 6.47 (d,J = 1.9 Hz, 1H), 5.69-5.74 (m, 1H), 5.69-5.74 (m, 1H), 3.94 (s, 3H),3.85 (s, 3H), 3.07 (br. s., 2H), 2.68 (s, 3H), 2.51 (br. s., 8H), 1.11(s, 9H) ESI-MS m/z: 599.5 [M + H]⁺ 42

N-(2,4-dimethoxy-5-((4-(1-methyl-1H-indol-3-yl)-5-pivalamidopyrimidin-2- yl)amino)phenyl)acrylamide ¹H NMR:(CDCl₃) δ 9.64 (s, 1H), 9.23 (s, 1H), 8.41 (s, 1H), 7.74 (s, 1H), 7.56(d, J = 7.9 Hz, 2H), 7.45 (s, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.24-7.29(m, 2H), 7.15-7.21 (m, 1H), 6.53 (s, 1H), 6.39- 6.45 (m, 1H), 6.26-6.35(m, 1H), 5.73 (dd, J = 9.9, 1.3 Hz, 1H), 3.94 (s, 3H), 3.87 (s, 6H),1.12 (s, 9H) ESI-MS m/z: 529.5 [M + H]⁺

Example 43N-(5-((5-chloro-4-(1-methyl-1,6,7,8-tetrahydrocyclopenta[g]indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

A solution ofN4-(5-chloro-4-(1-methyl-1,6,7,8-tetrahydrocyclopenta[g]indol-3-yl)pyrimidin-2-yl)-N1-(2-(dimethylamino)ethyl)-5-methoxy-N1-methylbenzene-1,2,4-triamine(R7) (190 mg, 0.20 mmol) and DCM (25 mL) was cooled to 0° C.Subsequently, acryloyl chloride (36 mg, 0.20 mmol) was added dropwise at0° C. and stirred for 10 min before adding water (5 mL). The mixture wasconcentrated in vacuo and the resulting residue was purified by flashcolumn chromatography on silica gel (5% to 10% MeOH/DCM) to affordN-(5-((5-chloro-4-(1-methyl-1,6,7,8-tetrahydrocyclopenta[g]indol-3-yl)pyrimidin-2-yl)amino)₂-((2-(dimethylamino)ethyl)-(methyl)amino)-4-methoxyphenyl)acrylamide(Example 43) as light brown solid. ¹H-NMR: (CDCl₃) δ 10.06 (s, 1H), 9.55(s, 1H), 8.45 (s, 1H), 8.22 (s, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.58 (s,1H), 7.12 (d, J=8.4 Hz, 1H), 6.81 (s, 1H), 6.42 (dd, J=16.8, 1.6 Hz,1H), 6.34 (m, 1H), 5.69 (d, J=11.6 Hz, 1H), 4.09 (s, 3H), 3.90 (s, 3H),3.48 (t, J=7.2 Hz, 2H), 3.04 (t, J=7.6 Hz, 2H), 2.91 (in, 2H), 2.73 (s,3H), 2.30 (s, 61H), 2.26 (m, 2H), 2.22 (in, 2H). MS m/z 574.5 [M+H]⁺.

The following example compounds, as shown in Table 27, were synthesizedin analogous fashion to Example 43.

TABLE 27 Ex. Compound Amine compound 44

(R)-N-(5-((5-chloro-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((1-(dimethylamino)-3-ethoxypropan-2-yl)oxy)- 4-methoxyphenyl)acrylamide ¹HNMR: (CDCl₃) δ 9.84 (s, 1H), 9.37 (s, 1H), 8.34 (s, 1H), 8.32 (d, J =8.0 Hz, 1H), 8.26 (s, 1H), 7.42 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.20(m, 1H), 7.14 (m, 1H), 6.90 (s, 1H), 6.33 (d, J = 15.6 Hz, 1H), 6.22(dd, J = 16.8, 10.4 Hz, 1H), 5.62 (d, J = 8.8 Hz, 1H), 4.00 (m, 1H),3.83 (s, 3H), 3.79 (s, 3H), 3.58-3.53 (m, 5H), 2.78 (m, 1H), 2.25 (s,6H), 1.20 (t, J = 6.8 Hz, 3H) ESI-MS m/z: 579.4 [M + H]⁺ 45

N-(5-((5-chloro-4-(1-methyl-1H-indol-3- yl)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)prop-1-yn-1-yl)-4- methoxyphenyl)acrylamide ¹H NMR:(CDCl₃) δ 9.59 (s, 1H), 8.49 (s, 1H), 8.45 (d, J = 8.0 Hz, 1H), 8.34 (s,1H), 7.91 (s, 1H), 7.83 (s, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.34-7.25 (m,2H), 6.95 (s, 1H), 6.40 (dd, J = 16.8, 1.6 Hz, 1H), 6.29 (66, J = 16.8,10.0 Hz, 1H), 5.76 (d, J = 9.6 Hz, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.61(s, 2H), 2.44 (s, 6H) MS m/z 515.5 [M + H]⁺ 46

N-(5-((5-chloro-4-(1-methyl-1H-indol-3- yl)pyrimidin-2-yl)amino)-2-(3-(dimethylamino)-3-methylbut-1-yn-1-yl)-4- methoxyphenyl)acrylamide ¹HNMR: (CDCl₃) δ 9.53 (s, 1H), 8.49 (s, 1H), 8.46 (d, J = 8.0 Hz, 1H),8.39 (s, 1H), 8.00 (s, 1H), 7.85 (s, 1H), 7.40 (d, J = 8.0 Hz, 1H),7.35-7.26 (m, 2H), 6.93 (s, 1H), 6.42-6.30 (m, 2H), 5.77 (dd, J = 10.4,2.0 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 2.51 (s, 6H), 1.61 (s, 6H) MSm/z 543.5 [M + H]⁺ 47

N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-2-((1-(diethylamino)-3-methoxypropan-2-yl)oxy)- 4-methoxyphenyl)acrylamide ¹HNMR: (CDCl₃) δ 9.29 (s, 2H), 8.93 (s, 1H), 8.53 (t, 2H), 8.43 (s, 1H),7.38 (s, 1H), 7.32-7.26 (m, 1H), 6.98 (s, 1H), 6.90 (t, 1H), 6.33 (dd,2H), 5.68 (d, 1H), 3.89 (s, 3H), 3.71-3.54 (m, 3H), 3.41 (s, 3H), 3.06-2.83 (m, 6H), 0.98-0.93 (m, 6H) MS m/z 580.2 [M + H]⁺ 48

N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-2-((1- (dimethylamino)-3-methoxypropan-2-yl)oxy)-4-methoxyphenyl)acrylamide ¹H NMR: (CDCl₃) δ 9.29 (s, 1H), 8.94(s, 1H), 8.53 (t, 2H), 8.43 (s, 1H), 7.38 (s, 1H), 7.31 (t, 1H), 7.00(s, 1H), 6.90 (t, 1H), 6.39- 6.35 (m, 2H), 5.68 (d, 1H), 5.30 (s, 1H),3.89 (s, 3H), 3.60-3.57 (m, 2H), 3.43 (s, 3H), 2.51 (br, 6H), 1.69 (br,3H) MS m/z 552.2 [M + H]⁺ 49

N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(2-(pyrrolidin-1-yl)ethoxy)phenyl)acrylamide ¹H NMR: (DMSO-d₆) δ 10.14 (s,1H), 8.70 (s, 1H), 8.25 (d, J = 5.4 Hz, 1H), 7.98- 7.85 (m, 2H), 7.13(d, J = 5.4 Hz, 1H), 7.01 (s, 1H), 6.96-6.77 (m, 2H), 6.37 (dd, J =16.9, 10.1 Hz, 1H), 6.17 (dd, J = 16.9, 2.0 Hz, 1H), 5.79-5.66 (m, 1H),5.10 (d, J = 3.4 Hz, 1H), 4.53-4.02 (m, 4H), 3.81 (s, 3H), 3.27 (td, J =20, 2.0 Hz, 1H), 3.15 (d, J = 4.4 Hz, 1H), 2.88 (s, 4H), 2.70 (d, J =18.6 Hz, 3H), 2.30 (t, J = 4.0 Hz, 3H), 2.20 (s, 6H), 2.15-2.03 (m, 3H),1.92-1.89 (m, 1H) MS m/z 534.2 [M + H]⁺ 50

N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(2-morpholinoethoxy)phenyl)acrylamide ¹H NMR: (CDCl₃) δ 9.21 (s, 1H), 8.93(s, 1H), 8.53-8.51 (m, 2H), 8.41 (s, 1H), 8.32 (s, 1H), 7.29 (s, 1H),6.90 (t, 1H), 6.62 (s, 1H), 6.36-6.34 (m, 2H), 5.73 (d, 1H), 4.20 (t,2H), 3.88 (s, 3H), 3.77 (s, 4H), 2.73 (t, 2H), 2.57 (s, 4H) MS m/z 550.2[M + H]⁺ 51

N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-2-(2- (dimethylamino)ethoxy)-4-methoxyphenyl)acrylamide ¹H NMR: (CDCl₃) δ 9.63 (s, 1H), 9.23 (s, 1H),8.93 (s, 1H), 8.54-8.51 (m, 2H), 8.42 (s, 1H), 7.32-7.26 (m, 2H),6.91-6.88 (m, 1H), 6.64 (s, 1H), 6.35 (s, 1H), 5.68 (t, 1H), 4.16 (t,1H), 3.87 (s, 3H), 2.68 (br, 2H), 2.43 (s, 6H) MS m/z 508.2 [M + H]⁺ 52

N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)-(methyl)amino)-4-methoxyphenyl)-acrylamide ¹H NMR: (DMSO-d₆) δ 10.08 (s, 1H), 8.95 (s,1H), 8.82 (d, 1H), 8.73 (s, 1H), 8.43- 8.37 (m, 3H), 7.29 (t, 1H), 7.10(t, 1H), 7.05 (s, 1H), 6.39 (dd, 1H), 6.17 (dd, 1H), 5.72 (d, 1H), 3.76(s, 3H), 2.90 (t, 2H), 2.75 (s, 3H), 2.34 (t, 2H), 2.20 (s, 6H) MS m/z521.2 [M + H]⁺ 53

N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-2-((2- (diethylamino)ethyl)-(methyl)amino)-4-methoxyphenyl)acrylamide ¹H NMR: (CDCl₃) δ 9.62 (s, 1H), 9.38 (s, 1H),8.93 (s, 1H), 8.56-8.51 (m, 2H), 8.45 (s, 1H), 7.42 (s, 1H), 7.26 (t,1H), 6.89 (d, 1H), 6.79 (s, 1H), 6.35-6.30 (m, 2H), 5.68 (t, 1H), 3.87(s, 3H), 2.88 (t, 2H), 2.69 (s, 3H), 2.59 (dd, 4H), 2.47 (t, 2H), 1.03(t, 6H) MS m/z 549.4 [M + H]⁺ 54

N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-4-methoxy-2-(methyl(2-morpholinoethyl)amino)phenyl)- acrylamide ¹H NMR: (CDCl₃) δ9.40 (s, 1H), 9.15 (s, 1H), 8.94 (s, 1H), 8.56-8.53 (m, 2H), 8.47 (s,1H), 7.49 (s, 1H), 7.31-7.26 (m, 1H), 6.93-6.89 (m, 1H), 6.79 (s, 1H),6.39 (s, 2H), 5.73 (t, 1H), 3.87 (s, 3H), 3.73 (s, 4H), 3.01 (s, 2H),2.68 (s, 3H), 2.44-2.36 (m, 6H) MS m/z 563.4 [M + H]⁺ 55

N-(5-((5-chloro-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl)amino)-2-(3- (dimethylamino)pyrrolidin-1-yl)-4-methoxyphenyl)acrylamide ¹H NMR: (DMSO-d₆) δ 9.42 (s, 1H), 8.94 (s, 1H),8.20 (d, 1H), 8.57 (s, 1H), 8.37 (s, 1H), 7.63 (s, 1H), 7.38 (t, 1H),7.10 (t, 1H), 6.62 (s, 2H), 6.16 (d, 1H), 5.76 (s, 1H), 5.67 (d, 1H),3.78 (s, 3H), 3.36-3.27 (m, 6H), 2.44 (s, 5H), 2.18 (s, 1H), 1.98 (s,1H) MS m/z 533.3 [M + H]⁺ 56

N-(5-((5-chloro-4-(1H-indol-3-yl)pyrimidin-2- yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4- methoxyphenyl)acrylamide ¹H NMR:(DMSO-d₆) δ 11.67 (s, 1H), 10.15 (s, 1H), 8.75 (s, 1H), 8.61 (s, 1H),8.51 (s, 1H), 8.27 (d, 1H), 8.12 (s, 1H), 7.48 (d, 1H), 7.31 (s, 1H),7.16 (m, 2H), 7.02 (s, 1H), 6.43 (m, 1H), 6.37 (m, 1H), 5.76 (m, 1H),3.86 (s, 3H), 2.89 (m, 2H), 2.72 (s, 3H), 2.32 (m, 2H), 2.21 (s, 6H) MSm/z 486.2 [M + H]⁺ 59

isopropyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-methyl-1H-indazol-3-yl)pyrimidine-5-carboxylate ¹H NMR: (CDCl₃) δ 9.84 (br. s.,1H), 9.56 (br. s., 1H), 8.95 (s, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.91 (s,1H), 7.35-7.43 (m, 1H), 7.19 (m, 1H), 6.75 (s, 1H), 6.33-6.57 (m, 2H),6.06-6.32 (m, 1H), 5.61-5.75 (m, 2H), 5.02-5.13 (m, 1H), 4.12 (s, 3H),3.84 (s, 3H), 2.96 (t, J = 5.6 Hz, 2H), 2.66 (s, 3H), 2.51 (t, J = 5.6Hz, 2H), 2.37 (s, 6H), 1.13 (d, J = 6.3 Hz, 6H) ESI-MS m/z: 587.3 [M +H]⁺ 60

N-(2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indazol-3-yl)-5- propionamidopyrimidin-2-yl)amino)phenyl)acrylamide ¹H NMR: (MeOH-d₄) δ 9.42 (s, 1H), 8.57 (d, J= 8.3 Hz, 1H), 8.39 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.46 (ddd, J =8.4, 7.1, 1.0 Hz, 1H), 7.21-7.27 (m, 1H), 6.98 (s, 1H), 6.78- 6.79 (m,1H), 6.44-6.49 (m, 2H), 5.79-5.86 (m, 1H), 4.20 (s, 3H), 4.01 (s, 3H),3.48 (t, J = 5.6 Hz, 2H), 3.23-3.27 (m, 2H), 2.85 (s, 6H), 2.73 (s, 3H),2.56 (q, J = 7.5 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H) ESI-MS m/z: 572.3[M + H]⁺ 61

isopropyl (R)-2-((5-acrylamido-2-methoxy-4-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)amino)-4-(1H-indol- 1-yl)pyrimidine-5-carboxylate¹H NMR: (CDCl₃) δ 9.90 (br. s., 1H), 9.62 (s, 1H), 9.03 (br. s., 1H),7.81 (br. s., 1H), 7.58 (d, J = 7.4 Hz, 2H), 7.50 (d, J = 17.4 Hz, 1H),7.15 (br. s., 2H), 6.65-6.73 (m, 3H), 6.46-6.53 (m, 1H), 6.29-6.38 (m,1H), 5.72 (d, J = 10.3 Hz, 1H), 4.90 (br. s., 1H), 3.87 (s, 3H), 3.10(br. s., 1H), 2.85 (m, 1H), 2.74 (s, 3H), 2.66 (br. s., 2H), 2.56 (s,3H), 2.36 (m, 2H), 1.98 (m, 1H), 1.73 (br. s., 2H), 1.39 (br. s., 1H)ESI-MS m/z: 598.3 [M + H]⁺ 62

isopropyl (R)-2-((5-acrylamido-2-methoxy-4-(methyl((1-methylpyrrolidin-2- yl)methyl)amino)phenyl)amino)-4-(benzofuran-3-yl)pyrimidine-5-carboxylate ¹H NMR: (CDCl₃) δ 9.79 (s,1H), 9.36 (br. s., 1H), 9.03 (s, 1H), 8.72 (br. s., 1H), 7.91 (s, 1H),7.57-7.66 (m, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.17-7.34 (m, 3H),6.74-6.74 (m, 1H), 6.71 (s, 1H), 6.49-6.56 (m, 1H), 6.52 (dd, J = 16.8,1.6 Hz, 1H), 5.73-5.80 (m, 1H), 4.95-5.04 (m, 1H), 3.89 (s, 3H), 3.14-3.31 (m, 2H), 2.75 (s, 3H), 2.57 (s, 3H), 2.15 (m, 3H), 1.75 (br. s.,1H), 0.95-1.13 (m, 6H) ESI-MS m/z: 599.3 [M + H]⁺ 63

methyl (R)-2-((5-acrylamido-2-methoxy-4- (methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)amino)-4-(1H-indol- 1-yl)pyrimidine-5-carboxylate¹H NMR: (MeOH-d₄) δ 8.93 (s, 1H), 8.75- 8.75 (m, 1H), 8.73 (br. s., 1H),7.66 (d, J = 7.3 Hz, 1H), 7.53-7.59 (m, 2H), 7.09-7.18 (m, 2H), 6.97 (s,1H), 6.61-6.67 (m, 1H), 6.45-6.55 (m, 1H), 6.33-6.43 (m, 1H), 5.81 (dd,J = 10.0, 1.5 Hz, 1H), 3.93 (s, 3H), 3.63 (s, 3H), 3.11-3.05 (m, 3H),2.73 (s, 3H), 2.63-2.69 (m, 1H), 2.56 (s, 3H), 2.13 (m, 1H), 1.84-1.95(m, 2H), 1.60-1.70 (m, 1H) ESI-MS m/z: 570.3 [M + H]⁺ 64

isopropyl (R)-2-((5-acrylamido-2-methoxy-4-(methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)amino)-4-(1H-indol- 3-yl)pyrimidine-5-carboxylate¹H NMR: (CDCl₃) δ 9.72 (s, 1H), 9.14 (br. s., 1H), 8.91 (s, 1H), 8.24(br. s., 1H), 7.82 (s, 1H), 7.72 (d, J = 3.8 Hz, 1H), 7.30 (dd, J = 6.5,2.0 Hz, 1H), 7.04-7.16 (m, 2H), 6.71 (s, 1H), 6.45 (d, J = 15.3 Hz, 1H),5.62-5.74 (m, 1H), 4.92-5.05 (m, 1H), 3.85 (s, 3H), 3.09-3.21 (m, 1H),2.92 (br. s., 1H), 2.71 (s, 3H), 2.50 (s, 3H), 2.33-2.40 (m, 1H), 1.96(m, 1H), 1.74 (br. s., 2H), 1.45 (br. s., 1H), 1.04 (m, 6H) ESI-MS m/z:598.3 [M + H]⁺ 65

ethyl (R)-2-((5-acrylamido-2-methoxy-4- (methyl((1-methylpyrrolidin-2-yl)methyl)amino)phenyl)amino)-4-(1- methyl-1H-indol-3-yl)pyrimidine-5-carboxylate ¹H NMR: (CDCl₃) δ 9.80 (s, 1H), 9.75 (br. s., 1H), 8.90 (s,1H), 8.68 (br. s., 1H), 7.84 (s, 1H), 7.53 (d, J = 10.5 Hz, 1H), 7.32(d, J = 8.0 Hz, 2H), 7.16-7.24 (m, 1H), 7.08-7.15 (m, 1H), 6.73 (s, 1H),6.43-6.51 (m, 1H), 6.38 (d, J = 10.0 Hz, 1H), 5.72 (d, J = 11.8 Hz, 1H),4.11 (q, J = 7.0 Hz, 2H), 3.93 (s, 3H), 3.87 (s, 3H), 3.07 (m, 1H), 2.89(m, 1H), 2.72 (s, 3H), 2.57-2.69 (m, 2H), 2.52 (s, 3H), 2.26-2.37 (m,1H), 1.87-2.01 (m, 1H), 1.72 (m, 2H), 1.37-1.47 (m, 1H), 0.94 (t, J =6.7 Hz, 3H) ESI-MS m/z: 598.3 [M + H]⁺ 66

isopropyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carboxylate ¹H NMR: (CDCl₃) δ 10.09-10.19(m, 1H), 9.71 (s, 1H), 8.97 (s, 1H), 8.65 (br. s., 1H), 8.32 (d, J = 3.6Hz, 1H), 8.09 (br. s., 1H), 7.89 (s, 1H), 7.12 (dd, J = 7.8, 4.7 Hz,1H), 6.80 (s, 1H), 6.41-6.50 (m, 1H), 6.24-6.38 (m, 1H), 5.61-5.75 (m,1H), 5.05 (m, 1H), 3.88 (s, 3H), 2.87 (t, J = 5.5 Hz, 2H), 2.71 (s, 3H),2.20-2.33 (m, 8H), 1.11 (d, J = 6.4 Hz, 6H) ESI-MS m/z: 573.3 [M + H]⁺67

isopropyl 2-((5-acrylamido-4-(2- (dimethylamino)ethoxy)-2-methoxyphenyl)amino)-4-(1-methyl-1H- indol-3-yl)pyrimidine-5-carboxylate¹H NMR: (CDCl₃) δ 9.67-9.79 (m, 2H), 8.88 (s, 1H), 8.59 (br. s., 1H),7.81 (s, 1H), 7.59 (br. s., 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.20 (td, J =7.6, 0.9 Hz, 1H), 7.10-7.15 (m, 1H), 6.63 (s, 1H), 6.43-6.50 (m, 1H),6.24- 6.33 (m, 1H), 5.72 (dd, J = 10.2, 1.6 Hz, 1H), 4.96-5.05 (m, 1H),4.11 (t, J = 5.1 Hz, 2H), 3.92 (s, 3H), 3.86 (s, 3H), 2.54 (t, J = 5.1Hz, 2H), 2.34 (s, 6H), 1.03 (d, J = 6.1 Hz, 6H) ESI-MS m/z: 573.3 [M +H]⁺ 68

methyl 2-((5-acrylamido-4-(3- (dimethylamino)prop-1-yn-1-yl)-2-methoxyphenyl)amino)-4-(1-methyl-1H- indol-3-yl)pyrimidine-5-carboxylate¹H NMR: (CDCl₃) δ 9.77 (br. s., 1H), 8.91 (s, 1H), 8.55-8.69 (m, 1H),8.62 (br. s., 1H), 7.97 (br. s., 1H), 7.54 (d, J = 6.9 Hz, 1H), 7.34 (d,J = 8.2 Hz, 1H), 7.22 (td, J = 7.6, 1.0 Hz, 1H), 7.13-7.18 (m, 1H), 6.91(s, 1H), 6.41-6.47 (m, 1H), 6.27-6.35 (m, 1H), 5.78 (d, J = 10.2 Hz,1H), 3.94 (s, 3H), 3.89 (s, 3H), 3.64 (s, 3H), 3.58 (s, 2H), 2.41 (s,6H) ESI-MS m/z: 539.2 [M + H]⁺ 69

methyl 2-((5-acrylamido-4-(3- (dimethylamino)propyl)-2-methoxyphenyl)amino)-4-(1-methyl-1H- indol-3-yl)pyrimidine-5-carboxylate¹H NMR: (CDCl₃) δ 10.94 (br. s., 1H), 9.29 (br. s., 1H), 8.89 (s, 1H),8.46-8.59 (m, 1H), 7.96 (s, 1H), 7.53 (d, J = 9.8 Hz, 1H), 7.34 (d, J =8.0 Hz, 1H), 7.22 (t, J = 7.0 Hz, 1H), 7.11-7.18 (m, 1H), 6.66 (s, 1H),6.43-6.50 (m, 1H), 6.47 (dd, J = 16.9, 1.8 Hz, 1H), 6.22 (dd, J = 16.9,10.2 Hz, 1H), 5.71 (dd, J = 10.2, 1.9 Hz, 1H), 3.94 (s, 3H), 3.88 (s,3H), 3.63 (s, 3H), 2.65-2.71 (m, 2H), 2.26 (s, 6H), 2.13 (t, J = 5.6 Hz,2H), 1.87 (m, 2H) ESI-MS m/z: 543.3 [M + H]⁺ 70

N-(5-((4-(1-(2-amino-2-oxoethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide ¹H NMR: (CDCl₃): δ 10.27 (br. s., 1H), 9.77 (s,1H), 9.32 (s, 1H), 8.39 (d, J = 5.3 Hz, 1H), 8.02 (dd, J = 6.1, 2.5 Hz,1H), 7.76 (s, 1H), 7.44-7.51 (m, 1H), 7.28-7.33 (m, 2H), 7.21 (d, J =5.3 Hz, 1H), 6.80 (s, 1H), 6.46 (br. s., 1H), 6.37 (m, 2H), 5.69-5.74(m, 1H), 5.53 (br. s., 1H), 5.03 (s, 2H), 3.88 (s, 3H), 2.90 (t, J = 5.5Hz, 2H), 2.70 (s, 3H), 2.25 (s, 8H) ESI-MS m/z: 543.4 [M + H]⁺ 71

N-(5-((4-(1-(2-amino-2-oxoethyl)-1H-indol-3-yl)-5-ethylpyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4- methoxyphenyl)acrylamide ¹H NMR:(CDCl₃) δ 10.11 (br. s., 1H), 9.69 (s, 1H), 8.41 (s, 1H), 8.23 (s, 1H),7.73 (d, J = 7.9 Hz, 1H), 7.63 (s, 1H), 7.40 (d, J = 8.2 Hz, 1H),7.27-7.31 (m, 1H), 7.18-7.24 (m, 1H), 6.77 (s, 1H), 6.22-6.36 (m, 2H),6.07 (br. s., 1H), 5.64-5.72 (m, 1H), 5.33 (br. s., 1H), 4.96 (s, 2H),3.87 (s, 3H), 2.86 (t, J = 5.5 Hz, 2H), 2.79 (q, J = 7.6 Hz, 2H), 2.68(s, 3H), 2.18-2.28 (m, 8H), 1.11 (t, J = 7.6 Hz, 3 H) ESI-MS m/z: 543.4[M + H]⁺ 72

N-(2-((2- (dimethylamino)ethyl)(methyl)amino)-5-((5-ethyl-4-(1-(2-(methylamino)-2-oxoethyl)-1H-indol-3-yl)pyrimidin-2-yl)amino)-4- methoxyphenyl)acrylamide ¹H NMR:(CDCl₃) δ 10.12 (br. s., 1H), 9.70 (s, 1H), 8.42 (s, 1H), 8.22 (br. s.,1H), 7.75 (d, J = 7.8 Hz, 1H), 7.62 (s, 1H), 7.33-7.38 (m, 1H),7.18-7.24 (m, 1H), 6.78 (s, 1H), 6.25-6.36 (m, 2H), 5.96 (br. s., 1H),5.66- 5.73 (m, 1H), 4.97 (s, 2H), 3.87 (s, 3H), 2.86 (br. s., 2H), 2.79(q, J = 7.6 Hz, 2H), 2.66-2.69 (m, 6H), 2.23 (s, 8H), 1.14 (t, J = 7.6Hz, 3H) ESI-MS m/z: 585.3 [M + H]⁺ 75

methyl 2-((5-acrylamido-4-fluoro-2- methoxyphenyl)amino)-4-(1-(dimethylamino)-1H-indol-3-yl)pyrimidine-5- carboxylate ¹H NMR: (CDCl₃)δ 9.45 (d, J = 8.8 Hz, 1H), 8.91 (s, 1H), 8.72 (s, 1H), 8.05 (s, 1H),7.72 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 8.4 Hz, 1H), 7.16(t, J = 8.4 Hz, 1H), 6.75 (d, J = 12.0 Hz, 1H), 6.50 (dd, J = 17.2, 1.2Hz, 1H), 6.31 (dd, J = 17.2, 10.0 Hz, 1H), 5.84 (d, J = 10.0 Hz, 1H),3.92 (s, 3H), 3.66 (s, 3H), 3.05 (s, 6H ESI-MS m/z: 505.1 [M + H]⁺ 76

methyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1- (dimethylamino)-1H-indol-3-yl)pyrimidine-5-carboxylate ¹H NMR: (MeOH-d₄) δ 9.20 (s, 1H), 8.82 (s, 1H), 8.62 (m,1H), 7.58 (dd, J = 8.0, 0.8 Hz, 1H), 7.21 (td, J = 7.2, 0.8 Hz, 1H),7.10 (td, J = 8.0, 1.2 Hz, 1H), 7.00 (s, 1H), 6.57 (dd, J = 16.8, 10.0Hz, 1H), 6.41 (dd, J = 16.8, 1.2 Hz, 1H), 5.83 (dd, J = 10.0, 1.6 Hz,1H), 3.94 (s, 3H), 3.69 (s, 3H), 3.07 (t, J = 5.6 Hz, 2H), 3.00 (s, 6H),2.71 (s, 3H), 2.48 (m, 2H), 2.32 (s, 6H) ESI-MS m/z: 587.2 [M + H]⁺ 77

isopropyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-ethyl-1H-indol- 3-yl)pyrimidine-5-carboxylate¹H NMR: (MeOH-d₄) δ 9.32 (s, 1H), 8.77 (s, 1H), 8.34 (s, 1H), 7.64 (d, J= 8.0 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.23 (td, J = 8.0, 0.8 Hz, 1H),7.12 (td, J = 8.4, 0.8 Hz, 1H), 7.00 (s, 1H), 6.58 (dd, J = 16.8, 10.0Hz, 1H), 6.42 (dd, J = 16.8, 1.6 Hz, 1H), 5.82 (dd, J = 10.0, 1.6 Hz,1H), 4.98 (sep, J = 6.4 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 3.96 (s, 3H),3.07 (t, J = 5.6 Hz, 2H), 2.72 (s, 3H), 2.47 (m, 2H), 2.31 (s, 6H), 1.52(t, J = 7.2 Hz, 3H), 1.06 (d, J = 6.4 Hz, 6H) ESI-MS m/z: 600.3 [M + H]⁺78

isopropyl 4-(1-acetyl-1H-indol-3-yl)-2-((5- acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2- methoxyphenyl)amino)pyrimidine-5-carboxylate ¹H NMR: (MeOH-d₄) δ 9.25 (s, 1H), 8.94 (s, 1H), 8.47 (d, J =8.4 Hz, 1H), 8.38 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.36 (td, J = 8.4,1.2 Hz, 1H), 7.28 (td, J = 8.0, 1.2 Hz, 1H), 7.00 (s, 1H), 6.58 (dd, J =17.2, 10.0 Hz, 1H), 6.33 (dd, J = 17.2, 2.0 Hz, 1H), 5.80 (dd, J = 10.0,2.0 Hz, 1H), 4.93 (sep, J = 6.0 Hz, 1H), 3.96 (s, 3H), 3.08 (m, 2H),2.78 (s, 3H), 2.71 (s, 3H), 2.49 (m, 2H), 2.32 (s, 6H), 1.00 (d, J = 6.0Hz, 6H) ESI-MS m/z: 614.3 [M + H]⁺ 79

isopropyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(1-cyclopropyl-1H-indol-3-yl)pyrimidine-5-carboxylate ¹H NMR: (DMSO-d₆) δ 10.15 (s.,1H), 8.76 (d, J = 4.4 Hz, 1H), 1H), 8.68 (s, 1H), 8.01 (s, 1H), 7.70 (m,1H), 7.61 (d, J = 4.4 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.07-7.02 (m,2H), 6.42 (dd, J = 16.8, 5.6 Hz, 1H), 6.27 (dd, J = 16.8, 3.0 Hz, 1H),5.78 (dd, J = 10.0, 3.0 Hz, 1H), 4.96 (sep, J = 6.0 Hz, 1H), 3.81 (s,3H), 3.54 (m, 1H), 2.88 (t, J = 6.0 Hz, 2H), 2.73 (s, 3H), 2.32 (t, J =5.6 HZ, 2H), 2.21 (s, 6H), 1.11 (d, J = 6.0 Hz, 6H), 1.08 (m, 2H), 0.98(m, 2H). ESI-MS m/z: 612.3 [M + H]⁺ 80

methyl 3-(2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1- methyl-1H-indole-4-carboxylate ¹HNMR: (MeOH-d₄) δ 9.26 (d, J = 5.6 Hz, 1H), 8.11 (s, 1H), 7.71 (dd, J =8.4, 0.8 Hz, 1H), 7.53 (dd, J = 7.2, 0.8 Hz, 1H), 7.36 (dd, J = 8.4, 7.2Hz, 1H), 6.98 (s, 1H), 6.90 (d, J = 5.6 Hz, 1H), 6.53 (dd, J = 16.8,10.0 Hz, 1H), 6.33 (d, J = 16.8 Hz, 1H), 5.78 (d, J = 10.0 Hz, 1H),3.984 (s, 3H), 3.976 (s, 3H), 3.61 (s, 3H), 3.08 (m, 2H), 2.71 (s, 3H),2.48 (m, 2H), 2.34 (s, 6H) ESI-MS m/z: 558.2 [M + H]⁺ 81

methyl 3-(2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1- methyl-1H-indole-5-carboxylate ¹HNMR: (MeOH-d₄) δ 9.44 (s, 1H), 8.77 (s, 1H), 8.73 (s, 1H), 8.35 (d, J =5.6 Hz, 1H), 7.94 (dd, J = 8.8, 1.6 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H),7.25 (d, J = 5.6 Hz, 1H), 7.00 (s, 1H), 6.58 (dd, J = 16.8, 10.0 Hz,1H), 6.38 (dd, J = 16.8, 1.6 Hz, 1H), 5.80 (dd, J = 10.0, 1.6 Hz, 1H),3.983 (s, 3H), 3.976 (s, 3H), 3.96 (s, 3H), 3.08 (t, J = 6.0 Hz, 2H),2.73 (s, 3H), 2.49 (t, J = 6.0 Hz, 2H), 2.33 (s, 6H) ESI-MS m/z: 558.2[M + H]⁺ 82

methyl 3-(2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1- methyl-1H-indole-6-carboxylate ¹HNMR: (DMSO-d₆) δ 10.22 (s, 1H), 9.08 (s, 1H), 8.84 (s, 1H), 8.37 (d, J =5.2 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 1.6 Hz, 1H), 7.98(s, 1H), 7.75 (dd, J = 8.4, 1.6 Hz, 1H), 7.26 (d, J = 5.2 Hz, 1H), 7.06(s, 1H), 6.43 (dd, J = 16.8, 10.0 Hz, 1H), 6.25 (dd, J = 16.8, 2.0 Hz,1H), 5.77 (dd, J = 10.0, 2.0 Hz, 1H), 4.00 (s, 3H), 3.90 (s, 3H), 3.86(s, 3H), 2.97 (t, J = 5.6 Hz, 2H), 2.74 (s, 3H), 2.33 (m, 2H), 2.24 (s,6H) ESI-MS m/z: 558.2 [M + H]⁺ 83

methyl 3-(2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2methoxyphenyl)amino)pyrimidin-4-yl)-1- methyl-1H-indole-6-carboxylate ¹HNMR: (MeOH-d₄) δ 9.30 (s, 1H), 8.52 (s, 1H), 8.51 (d, J = 8.0 Hz, 1H),8.32 (d, J = 5.6 Hz, 1H), 7.62 (dd, J = 7.2, 1.2 Hz, 1H), 7.25-7.20 (m2H), 7.00 (s, 1H), 6.58 (dd, J = 16.8, 10.0 Hz, 1H), 6.38 (dd, J = 16.8,1.6 Hz, 1H), 5.80 (dd, J = 10.0, 1.6 Hz, 1H), 4.00 (s, 3H), 3.99 (s,3H), 3.96 (s, 3H), 3.09 (t, J = 6.0 Hz, 2H), 2.73 (s, 3H), 2.50 (m, 2H),2.34 (s, 6H) ESI-MS m/z: 558.2 [M + H]⁺ 84

isopropyl 3-(2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1- methyl-1H-indole-6-carboxylate ¹HNMR: (MeOH-d₄) δ 9.75 (s, 1H), 8.34 (d, J = 5.6 Hz, 1H), 8.31 (d, J =8.4 Hz, 1H), 8.17 (d, J = 1.6 Hz, 1H), 7.87 (dd, J = 8.4, 1.6 Hz, 1H),7.28 (d, J = 5.6 Hz, 1H), 7.25 (d, J = 5.6 Hz, 1H), 7.02 (s, 1H), 6.60(dd, J = 17.2, 10.4 Hz, 1H), 6.38 (dd, J = 17.2, 1.6 Hz, 1H), 5.80 (dd,J = 10.4, 1.6 Hz, 1H), 5.29 (sep, J = 6.4 Hz, 1H), 4.04 (s, 3H), 3.97(s, 3H), 3.11 (m, 2H), 2.74 (s, 3H), 2.50 (m, 2H), 2.3 (s, 6H), 1.44 (d,J = 6.4 Hz, 6H) ESI-MS m/z: 586.2 [M + H]⁺ 85

isopropyl 3-(2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1- methyl-1H-indole-7-carboxylate ¹HNMR: (MeOH-d₄) δ 9.29 (s, 1H), 8.53- 8.48 (m, 2H), 8.33 (d, J = 5.6 Hz,1H), 7.59 (dd, J = 7.2, 0.8 Hz, 1H), 7.26 (d, J = 7.2 Hz, 1H), 7.22 (t,J = 7.2 Hz, 1H), 7.00 (s, 1H), 6.59 (dd, J = 17.2, 10.0 Hz, 1H), 6.38(dd, J = 17.2, 1.6 Hz, 1H), 5.81 (dd, J = 10.0, 1.6 Hz, 1H), 5.32 (sep,J = 6.4 Hz, 1H), 4.00 (s, 3H), 3.96 (s, 3H), 3.10 (t, J = 6.0 Hz, 2H),2.73 (s, 3H), 2.51 (m, 2H), 2.35 (s, 6H), 1.45 (d, J = 6.4 Hz, 6H)ESI-MS m/z: 586.2 [M + H]⁺ 86

methyl 3-(2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1- methyl-1H-indole-2-carboxylate ¹HNMR: (MeOH-d₄) δ 9.02 (s, 1H), 8.47 (d, J = 5.2 Hz, 1H), 7.92 (d, J =8.0 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.40 (td, J = 8.4, 1.2 Hz, 1H),7.23 (td, J = 8.0, 1.2 Hz, 1H), 7.03 (d, J = 5.2 Hz, 1H), 6.97 (s, 1H),6.51 (dd, J = 16.8, 10.4 Hz, 1H), 6.31 (dd, J = 16.8, 1.6 Hz, 1H), 5.77(dd, J = 10.4, 1.6 Hz, 1H), 4.01 (s, 3H), 3.94 (s, 3H), 3.75 (s, 3H),3.06 (t, J = 6.0 Hz, 2H), 2.71 (s, 3H), 2.46 (m, 2H), 2.32 (s, 6H)ESI-MS m/z: 558.2 [M + H]⁺ 87

isopropyl 3-(2-((5-acrylamido-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1- methyl-1H-indole-2-carboxylate ¹HNMR: (MeOH-d₄) δ 9.10 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 7.85 (d, J =8.4 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.39 (ddd, J = 8.4, 6.8, 1.2 Hz,1H), 7.22 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.03 (d, J = 5.2 Hz, 1H),6.96 (s, 1H), 6.51 (dd, J = 16.8, 10.0 Hz, 1H), 6.32 (d, J = 16.8, 1.2Hz, 1H), 5.76 (dd, J = 10.0, 1.2 Hz, 1H), 5.08 (sep, J = 6.4 Hz, 1H),4.01 (s, 3H), 3.92 (s, 3H), 3.04 (t, J = 6.0 Hz, 2H), 2.70 (s, 3H), 2.43(t, J = 6.0 Hz, 2H), 2.30 (s, 6H), 1.20 (d, J = 6.4 Hz, 6H) ESI-MS m/z:586.2 [M + H]⁺ 88

N-(5-((4-(2-cyano-1-methyl-1H-indol-3- yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4- methoxyphenyl)acrylamide ¹H NMR:(MeOH-d₄) δ 9.10 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 7.85 (d, J = 8.4 Hz,1H), 7.55 (d, J = 8.4 Hz, 1H), 7.39 (ddd, J = 8.4, 6.8, 1.2 Hz, 1H),7.22 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.03 (d, J = 5.2 Hz, 1H), 6.96 (s,1H), 6.51 (dd, J = 16.8, 10.0 Hz, 1H), 6.32 (d, J = 16.8, 1.2 Hz, 1H),5.76 (dd, J = 10.0, 1.2 Hz, 1H), 5.08 (sep, J = 6.4 Hz, 1H), 4.01 (s,3H), 3.92 (s, 3H), 3.04 (t, J = 6.0 Hz, 2H), 2.70 (s, 3H), 2.43 (t, J =6.0 Hz, 2H), 2.30 (s, 6H), 1.20 (d, J = 6.4 Hz, 6H) ESI-MS m/z: 586.2[M + H]⁺ 89

N-(5-((4-(6-cyano-1-methyl-1H-indol-3- yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4- methoxyphenyl)acrylamide ¹H NMR:(MeOH-d₄) δ 8.79 (s, 1H), 8.50 (d, J = 8.4 Hz, 1H), 8.49 (s, 1H), 8.33(d, J = 5.2 Hz, 1H), 7.95 (s, 1H), 7.41 (dd, J = 8.4, 1.6 Hz, 1H), 7.23(d, J = 5.2 Hz, 1H), 7.00 (s, 1H), 6.56-6.50 (m, 2H), 5.91-5.87 (m, 1H),4.02 (s, 3H), 3.98 (s, 3H), 3.37 (s, 3H), 3.03 (m, 2H), 2.75 (s, 6H),2.72 (m, 2H) ESI-MS m/z: 586.2 [M + H]⁺ 90

3-(2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-1- methyl-1H-indole-2-carboxamide ¹HNMR: (MeOH-d₄) δ 8.85 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 8.13 (d, J =8.0 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.34 (ddd, J = 8.4, 7.2, 1.2 Hz,1H), 7.21 (ddd, J = 8.0, 7.2, 1.2 Hz, 1H), 7.15 (d, J = 5.2 Hz, 1H),6.98 (s, 1H), 6.51 (dd, J = 16.8, 10.0 Hz, 1H), 6.30 (d, J = 16.8, Hz,1H), 5.76 (d, J = 10.0 Hz, 1H), 3.95 (s, 6H), 3.10 (m, 2H), 2.72 (s,3H), 2.50 (m, 2H), 2.34 (s, 6H) ESI-MS m/z: 543.2 [M + H]⁺ 91

3-(2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-N,1-dimethyl-1H-indole-2-carboxamide ¹H NMR: (MeOH-d₄) δ 8.92 (s, 1H), 8.41(d, J = 5.2 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H),7.35 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.22 (td, J = 8.0, 1.2 Hz, 1H),7.06 (d, J = 5.2 Hz, 1H), 6.99 (s, 1H), 6.50 (dd, J = 17.2, 10.0 Hz,1H), 6.27 (d, J = 17.2, Hz, 1H), 5.75 (d, J = 10.0 Hz, 1H), 3.95 (s,3H), 3.89 (s, 3H), 3.10 (m, 2H), 2.80 (s, 3H), 2.72 (s, 3H), 2.50 (m,2H), 2.33 (s, 6H) ESI-MS m/z: 557.2 [M + H]⁺ 92

3-(2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-N,N,1-trimethyl-1H-indole-2-carboxamide ¹H NMR: (MeOH-d₄) δ 8.95 (s,1H), 8.41 (d, J = 5.2 Hz, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.55 (d, J =8.4 Hz, 1H), 7.35 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.26 (ddd, J = 8.4,7.2, 1.2 Hz, 1H), 7.10 (d, J = 5.2 Hz, 1H), 6.99 (s, 1H), 6.50 (dd, J =16.8, 10.0 Hz, 1H), 6.27 (d, J = 16.8, 1.2 Hz, 1H), 5.75 (dd, J = 10.0,1.2 Hz, 1H), 3.96 (s, 3H), 3.80 (s, 3H), 3.17 (s, 3H), 3.10 (m, 2H),2.80 (s, 3H), 2.84 (s, 3H), 2.72, (s, 3H), 2.50 (m, 2H), 2.34 (s, 6H)ESI-MS m/z: 571.3 [M + H]⁺ 93

3-(2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)-N-(2-methoxyethyl)-1-methyl-1H-indole-2- carboxamide ¹H NMR: (MeOH-d₄) δ 8.98(s, 1H), 8.40 (d, J = 5.6 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.51 (d, J= 8.4 Hz, 1H), 7.34 (ddd, J = 8.4, 7.2, 1.2 Hz, 1H), 7.21 (ddd, J = 8.0,7.2, 1.2 Hz, 1H), 7.10 (d, J = 5.6 Hz, 1H), 6.98 (s, 1H), 6.50 (dd, J =16.8, 10.4 Hz, 1H), 6.27 (d, J = 16.8, 1.6 Hz, 1H), 5.74 (dd, J = 10.0,1.6 Hz, 1H), 3.94 (s, 3H), 3.89 (s, 3H), 3.50 (s, 4H), 3.30 (s, 3H),3.07 (t, J = 6.0 Hz, 2H), 2.80 (s, 3H), 2.71 (s, 3H), 2.47 (t, J = 6.0Hz, 2H), 2.31 (s, 6H) ESI-MS m/z: 601.2 [M + H]⁺ 94

isopropyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(imidazo[1,2-a]pyridin-3-yl)pyrimidine-5-carboxylate ¹H NMR: (MeOH-d₄) δ 10.05 (br.,s, 1H), 9.42 (s, 1H), 9.11 (d, dt, J = 6.8, 0.8 Hz, 1H), 9.01 (s, 1H),8.20 (s, 1H), 7.70 (t, J = 0.8 Hz, 1H), 7.68 (s, 1H), 7.27 (m, 1H), 6.86(t, J = 6.8 Hz, 1H), 6.80 (s, 1H), 6.45-6.40 (m, 2H), 5.72 (m, 1H), 5.19(sep, J = 6.4 Hz, 1H), 3.89 (s, 3H), 2.96 (m, 2H), 2.74 (s, 3H), 2.37(m, 2H), 1.26 (d, J = 6.4 Hz, 6H) ESI-MS m/z: 573.3 [M + H]⁺ 95

  N-(2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-6-(1-methyl-1H-pyrazol-4-yl)-1H-indol-3-yl)pyrimidin-2-

yl)amino)phenyl)acrylamide ¹H NMR: (MeOH-d₄) δ 9.39 (s, 1H), 8.58 (s,1H), 8.31 (d, J = 5.6 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.00 (s, 1H),7.89 (s, 1H), 7.64 (s, 1H), 7.42 (dd, J = 8.4, 1.6 Hz, 1H), 7.26 (d, J =5.6 Hz, 1H), 7.01 (s, 1H), 6.61 (dd, J = 17.2, 10.0 Hz, 1H), 6.40 (dd, J= 17.2, 1.2 Hz, 1H), 5.80 (dd, J = 10.0, 1.6 Hz, 1H), 3.98 (s, 3H),3.976 (s, 3H), 3.974 (s, 3H), 3.10 (t, J = 6.0 Hz, 2H), 2.74 (s, 3H),2.50 (m, 2H), 2.34 (s, 6H) ESI-MS m/z: 580.2 [M + H]⁺ 96

N-(2-((2- (dimethylamino)ethyl)(methyl)amino)-5-((5-(dimethylphosphoryl)-4-(1-methyl-1H-indol- 3-yl)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide ¹H NMR: (MeOH-d₄) δ 8.80 (s, 1 H), 8.60 (d, J =8.0 Hz, 1 H), 8.31 (s, 1 H), 8.03 (d, J = 8.0 Hz, 1 H), 7.35 (d, J = 8.0Hz, 1 H), 7.14 (td, J = 8.0, 1.8 Hz, 1 H), 7.02 (t, J = 8.0 Hz, 1H),6.85 (s, 1H), 6.39 (dd, J = 17.2, 10.0 Hz, 1 H), 6.18 (dd, J =17.2, 1.6Hz, 1H), 5.65 (dd, J = 10.0, 1.6 Hz, 1H), 3.79 (s, 3H), 3.78 (s, 3 H),2.94 (t, J = 6.0 Hz, 2H), 2.58 (s, 3 H), 2.35 (t, J = 6.0 Hz, 2 H), 2.18(s, 6H), 1.58 (s, 3 H), 1.55 (s, 3 H) ESI-MS m/z: 576.2 [M + H]⁺ 97

isopropyl 2-((5-acrylamido-4-((2- (dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-4-(3-methyl-1H- indol-1-yl)pyrimidine-5-carboxylate¹H NMR: np ESI-MS m/z: 576.2 [M + H]⁺ 98

N-(5-((5-cyano-4-(1-methyl-1H-indazol-3- yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4- methoxyphenyl)acrylamide ¹H NMR:(CDCl₃) δ 10.16 (s, 1H), 8.80 (m, 1H), 8.50 (d, 1H), 7.82 (m, 1H), 7.45(m, 2H), 6.80 (m, 1H), 6.30 (m, 1H), 5.67 (d, 1H), 5.30 (m, 2H), 4.22(s, 3H), 3.90 (s, 3H), 2.88 (m, 2H), 2.74 (s, 3H), 2.33 (m, 6H), 1.42(m, 2H) ESI-MS m/z: 526.2 [M + H]⁺ 99

N-(2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)-5- (3-methylureido)pyrimidin-2-yl)amino)phenyl)acrylamide ¹H NMR: np ESI-MS m/z: 572.2 [M + H]⁺ 100

N-(2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-methyl-2-((2-oxoazetidin-1-yl)methyl)-1H-indol-3-yl)pyrimidin-2- yl)amino)phenyl)acrylamide ¹HNMR: (MeOH-d₄) δ 8.88 (s, 1H), 8.41 (d, J = 5.27 Hz, 1H), 7.95 (d, J =7.91 Hz, 1H), 7.48 (d, J = 8.28 Hz, 1H), 7.17-7.32 (m, 3H), 6.98 (s,1H), 6.48-6.60 (m, 1H), 6.32- 6.36 (m, 1H), 5.78 (dd, J = 1.57, 10.23Hz, 1H), 5.08 (s, 2H), 3.92 (s, 3H), 3.82 (s, 3H), 3.05 (t, J = 6.02 Hz,2H), 2.95 (t, J = 3.95 Hz, 2H), 2.79 (t, J = 3.95 Hz, 2H), 2.71 (s, 3H),2.47 (t, J = 5.96 Hz, 2H), 2.31 (s, 6H) ESI-MS m/z: 583.2 [M + H]⁺

Intermediate U1 tert-butyl(2-((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)ethyl)(methyl)carbamate

tert-butyl(2-((2-acrylamido-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)ethyl)(methyl)carbamatewas synthesized in analogous fashion to Example 1, except tert-butyl(2-((2-amino-5-methoxy-4-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)(methyl)amino)ethyl)(methyl)carbamate(03) was employed.

The following intermediate compounds, as shown in Table 28, weresynthesized in analogous fashion to Example 1.

TABLE 28 Intermediate U Aniline

Example 57N-(4-methoxy-2-(methyl(2-(methylamino)ethyl)amino)-5-((4-(1-methyl-1-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

To a solution of tert-butyl2-((2-acrylamido-5-methoxy-4-(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-ylamino)phenyl)methyl)amino)ethyl(methyl)carbamate(U1) (130 mg, 0.22 mmol) in DCM (2 mL) was added TFA (1 mL). The mixturewas stirred at rt for 10 min. Subsequently the mixture was concentratedin vacuo. The resulting residue was then diluted with DCM, washed with asaturated solution of potassium carbonate then brine, dried over sodiumsulfate, filtered, and concentrated in vacuo. The resulting residue waspurified by preparative thin layer chromatography on silica gel (5%MeOH/DCM) to affordN-(4-methoxy-2-(methyl(2-(methylamino)ethyl)amino)-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide(Example 57) as a yellow powder (52 mg, 48% yield). ¹H-NMR (DMSO-d₆) δ9.65 (s, 1H), 8.90 (br. s., 1H), 8.86 (s, 1H), 8.55 (s, 1H), 8.28-8.33(m, 21-), 7.89 (s, 1H), 7.51 (d, 2H), 7.16-7.24 (m, 3H), 7.0 (m, 1H),6.25-6.29 (d, 1H), 5.75 (m, 1H), 3.88 (s, 3H), 3.23 (m, 2H), 3.10 (m,2H), 2.59 (s, 3H), 2.58 (s, 3H). MS m/z 574.5 [M+H]⁺.

The following Example compounds, as shown in Table 29, were synthesizedin analogous fashion to Example 57.

TABLE 29 Example Compound Boc-protected Amine 58

isopropyl 2-((5-acrylamido-2- U2 methoxy-4-(methyl(2-(methylamino)ethyl)- amino)phenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine- 5-carboxylate ¹H NMR: (CDCl₃) δ 7.82(s, 1 H), 7.70 (br. s., 1 H), 7.33 (d, 1 H), 7.25 (d, 1 H), 7.18 (dd, 1H), 7.00 (dd, 1 H), 6.53 (s, 1 H), 6.37 (d, 1 H), 5.70 (d, 1 H), 5.04(m, 1 H), 3.87 (s, 6 H), 3.19 (s, 2 H), 2.84 (s, 2 H), 2.52 (s, 3 H),2.44 (s, 3 H), 1.06 (d, 6 H) MS m/z 573 [M + H]⁺ 73

isopropyl 2-((5-acrylamido-2- U3 methoxy-4-(methyl(2-(methylamino)ethyl)- amino)phenyl)amino)-4-(1-methyl-1H-indol-3-yl)pyrimidine- 5-carboxylate ¹H NMR: (CDCl₃) δ 9.57(br. s., 1H), 8.86 (s, 1H), 8.46 (br. s., 1H), 7.78 (s, 1H), 7.62 (br.s., 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.22 (t, J = 7.1 Hz, 1H), 7.07-7.15(m, 1H), 6.60-6.71 (m, 2H), 6.37 (d, J = 16.7 Hz, 1H), 5.64-5.73 (m,1H), 5.01 (dt, J = 12.5, 6.2 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.50(m, 1H), 3.03-3.12 (m, 1H), 2.90-2.99 (m, 1H), 2.82 (br. s., 2H), 2.63(s, 3H), 1.82-1.92 (m, 1H), 1.69-1.78 (m, 2H),1.24- 1.36 (m, 2H), 1.06(d, J = 6.1 Hz, 6H) ESI-MS m/z: 598.3 [M + H]⁺ 74

isopropyl 2-((5-acrylamido-2- U4 methoxy-4-(methyl(2-(methylamino)ethyl)amino)phenyl)amino)-4-(1-methyl-1H-pyrrolo[2,3-6]pyridin- 3-yl)pyrimidine-5-carboxylate ¹HNMR: (CDCl₃) δ 9.61 (s, 1H), 8.89 (s, 1H), 8.71 (br. s., 1H), 8.54 (d, J= 4.4 Hz, 1H), 8.33 (dd, J = 4.6, 1.5 Hz, 1H), 7.93 (br. s., 1H), 7.87(s, 1H), 7.09 (dd, J = 8.0, 4.7 Hz, 1H), 6.57-6.75 (m, 2H), 6.43 (dd, J= 16.9, 1.8 Hz, 1H), 5.65-5.77 (m, 1H), 5.05 (m, 1H), 4.00 (s, 3H), 3.87(s, 3H), 2.86-3.02 (m, 2H), 2.73 (t, J = 5.3 Hz, 2H), 2.64 (s, 3H), 2.47(s, 3H), 1.11 (d, J = 6.4 Hz, 6H) ESI-MS m/z: 573.3 [M + H]⁺

Biological Examples Example 101: ASV & NPG EGFR Exon 20 InsertionMutations

A compound's ability in selectively inhibiting EGFR exon 20 insertionmutations can be assessed using Ba/F3 cells, a murine pro-B cell line,which have been transduced with EGFR exon 20 insertions. An expressionvector, pLVX-IRES puro (Clontech) coding for human EGFR exon 20insertions NPG (H773_V774insNPG) or ASV(V769_D770insASV), wastransfected into HEK293 cells by the Trans-Lentiviral ORF PackagingSystem (Thermo Scientific), to produce virus encoding EGFR exon 20insertions. Ba/F3 (DSMZ) cells maintained in RPMI 1640 mediumsupplemented with 10% fetal bovine serum, 200 μM L-glutamine/200 μg/mLpenicillin/200 μg/mL streptomycin (Life Technology) and 10 ng/mL IL-3(R&D system), were infected by EGFR Exon20 virus and subsequentlyselected by puromycin (Life Technology) selection and IL-3 depletion.Ba/F3 cells expressing EGFR exon 20 insertions (namedBa/F3-EGFR-Exon20-NPG or Ba/F3-EGFR-Exon20-ASV) can proliferate in theabsence of IL-3. The anti-proliferative activity of compounds weredetermined as follows: BaF3-EGFR-Exon20 cells (NPG or ASV) seeded in 96well plates (2500 cells/well) were treated with test compound (dissolvedin DMSO) at a series of concentrations (4-fold dilution, topconcentration: 10,000 nM). The plates were incubated for 72 h in a 37°C. incubator with 5% CO₂, and the number of viable cells in each wellwere measured indirectly by CellTiter 96® Aqueous One Solution CellProliferation Assay (Promega) This assay is a colorimetric method fordetermining the number of viable cells through measurement of theirmetabolic activity by detection of enzymatic conversion of tetrazoliumsalts into blue formazan derivatives. Reagent (20 μL) was added intoeach well, and the plates were returned to the incubator for 2 h. Theabsorbance in each well was then measured at 490 nm using an Envisionplate reader (Perkin Elmer). IC₅₀ values were calculated by determiningthe concentration of compound required to decrease the MTS signal by 50%comparing to the DMSO control in best-fit curves using Microsoft XLfitsoftware or Accelrys Pipeline Pilot.

Example 102: EGFR Exon 19 Deletion and Exon 20 T790M ConcurrentMutations

A compound's ability in selectively inhibiting EGFR exon 19 deletion andT790M concurrent mutations can be assessed using Ba/F3 cells, a murinepro-B cell line, which have been transduced with EGFR exon 19 deletionand T790M mutation. An expression vector, pLVX-IRES puro (Clontech)coding for human EGFR E746-A750 deletion and T790M Mutation, wastransfected into HEK293 cells by the Trans-Lentiviral ORF PackagingSystem (Thermo Scientific), to produce virus encoding EGFR exon 19deletion and T790M mutations. Ba/F3 (DSMZ) cells maintained in RPMI 1640medium supplemented with 10% fetal bovine serum, 200 μM L-glutamine/200μg/mL penicillin/200 μg/mL streptomycin (Life Technology) and 10 ng/mLIL-3 (R&D system), were infected by EGFR E746-A750 deletion and T790MMutation virus and subsequently selected by puromycin (Life Technology)selection and IL-3 depletion. Ba/F3 cells expressing EGFR E746-A750deletion and T790M Mutation (named Ba/F3-EGFR-Del/T790M) can proliferatein the absence of IL-3. The anti-proliferative activity of compounds wasdetermined as follows: BaF3-EGFR-Del/T790M cells seeded in 96 wellplates (2500 cells/well) were treated with test compound (dissolved inDMSO) at a series of concentrations (4-fold dilution, top concentration:10,000 nM). The plates were incubated for 72 h in a 37° C. incubatorwith 5% CO₂, and the number of viable cells in each well were measuredindirectly by CellTiter 96® Aqueous One Solution Cell ProliferationAssay (Promega; this assay is a colorimetric method for determining thenumber of viable cells through measurement of their metabolic activityby detection of enzymatic conversion of tetrazolium salts into blueformazan derivatives). Reagent (20 μL) was added into each well, and theplates were returned to the incubator for 2 h. The absorbance in eachwell was then measured at 490 nm using an Envision plate reader (PerkinElmer). IC₅₀ values were calculated by determining the concentration ofcompound required to decrease the MTS signal by 50% comparing to theDMSO control in best-fit curves using Microsoft XLfit software orAccelrys Pipeline Pilot.

Example 103: EGFR Exon 21 L858R and Exon 20 T790M Concurrent Mutations

A compound's ability in selectively inhibiting EGFR L858R and T790Mconcurrent mutations can be assessed using Ba/F3 cells, a murine pro-Bcell line, which have been transduced with EGFR L858R and T790M doublemutations. An expression vector, pLVX-IRES puro (Clontech) coding forhuman EGFR L858R and T790M double mutation, was transfected into HEK293cells by the Trans-Lentiviral ORF Packaging System (Thermo Scientific),to produce virus encoding EGFR L858R and T790M double mutations. Ba/F3(DSMZ) cells maintained in RPMI 1640 medium supplemented with 10% fetalbovine serum, 200 μM L-glutamine/200 μg/mL penicillin/200 μg/mLstreptomycin (Life Technology) and 10 ng/mL IL-3 (R&D system), wereinfected by EGFR L858R and T790M double mutation virus and subsequentlyselected by puromycin (Life Technology) selection and IL-3 depletion.Ba/F3 cells expressing EGFR L858R and T790M double mutation (namedBa/F3-EGFR L858R/T790M) can proliferate in the absence of IL-3. Theanti-proliferative activity of compounds was determined as follows:BaF3-EGFR L858R/T790M cells seeded in 96 well plates (2500 cells/well)were treated with test compound (dissolved in DMSO) at a series ofconcentrations (4-fold dilution, top concentration: 10,000 nM). Theplates were incubated for 72 h in a 37° C. incubator with 5% CO₂, andthe number of viable cells in each well were measured indirectly byCellTiter 96 Aqueous One Solution Cell Proliferation Assay (Promega;this assay is a colorimetric method for determining the number of viablecells through measurement of their metabolic activity by detection ofenzymatic conversion of tetrazolium salts into blue formazanderivatives). Reagent (20 μL) was added into each well, and the plateswere returned to the incubator for 2 h. The absorbance in each well wasthen measured at 490 nm using an Envision plate reader (Perkin Elmer).IC₅₀ values were calculated by determining the concentration of compoundrequired to decrease the MTS signal by 50% comparing to the DMSO controlin best-fit curves using Microsoft XLfit software or Accelrys PipelinePilot.

Example 104: HER2 Exon 20 YVMA Insertion Mutation

A compound's ability in selectively inhibiting Her2 exon 20 YVMAinsertion mutations can be assessed using Ba/F3 cells, a murine pro-Bcell line, which have been transduced with Her2 Exon20 YVMA insertions.An expression vector, pLVX-IRES puro (Clontech) coding for human EGFRexon 20 insertions YVMA (A775_G776ins YVMA), was transfected into HEK293cells by the Trans-Lentiviral ORF Packaging System (Thermo Scientific),to produce virus encoding EGFR exon 20 insertions. Ba/F3 (DSMZ) cellsmaintained in RPMI 1640 medium supplemented with 10% fetal bovine serum,200 μM L-glutamine/200 μg/mL penicillin/200 μg/mL streptomycin (LifeTechnology) and 10 ng/mL IL-3 (R&D system), were infected by EGFR Exon20virus and subsequently selected by puromycin (Life Technology) selectionand IL-3 depletion. Ba/F3 cells expressing Her2 Exon20 YVMA insertions(named Ba/F3-Her2 Exon20 YVMA) can proliferate in the absence of IL-3.The anti-proliferative activity of compounds was determined as follows:BaF3-Her2 Exon20 YVMA cells seeded in 96 well plates (2500 cells/well)were treated with test compound (dissolved in DMSO) at a series ofconcentrations (4-fold dilution, top concentration: 10,000 nM). Theplates were incubated for 72 h in a 37° C. incubator with 5% CO₂, andthe number of viable cells in each well were measured indirectly byCellTiter 96® Aqueous One Solution Cell Proliferation Assay (Promega;this assay is a colorimetric method for determining the number of viablecells through measurement of their metabolic activity by detection ofenzymatic conversion of tetrazolium salts into blue formazanderivatives). Reagent (20 μL) was added into each well, and the plateswere returned to the incubator for 2 h. The absorbance in each well wasthen measured at 490 nm using an Envision plate reader (Perkin Elmer).IC₅₀ values were calculated by determining the concentration of compoundrequired to decrease the MTS signal by 50% comparing to the DMSO controlin best-fit curves using Microsoft XLfit software or Accelrys PipelinePilot.

Table 30 provides the ASV and NPG insertion mutant exon 20 EGFR IC₅₀data for exemplary compounds. IC₅₀ data on a DT mutation is provided,along with YVMA insertion mutant exon 20 HER2 IC₅₀ data for exemplarycompounds. Group A compounds have an IC₅₀ value for the indicated mutantbelow about 100 nM. Group B compounds have an IC₅₀ value for theindicated mutant between about 100 to about 500 nM. Group C compoundshave an IC₅₀ value for the indicated mutant between greater than about500 to about 1 μM. Group D compounds have an IC₅₀ value for theindicated mutant greater than about 1 μM. “ND” indicates data notpresented and should not be construed as the compound having anyparticular activity, such as, for example, Group D.

TABLE 30 EGFR EGFR EGFR EGFR exon 19 exon 21 Her2 exon 20 exon 20deletion and L858R and exon 20 ASV NPG T790M T790M YVMA insertioninsertion mutation mutation insertion Ex. IC₅₀ IC₅₀ IC₅₀ IC₅₀ IC₅₀ 1 NDA A ND B 2 A A A ND B 3 A A A ND B 4 B A B ND B 5 B B B B B 6 A A A ND B7 B A A A B 8 A A A ND A 9 A A A A A 10 A A A A A 11 A A A ND A 12 D D DND D 13 A A A ND A 14 A A A ND A 15 A A A ND A 16 A A A ND B 17 A A A AA 18 D B A ND D 19 B A A ND C 20 B A A ND C 21 C A A ND C 22 B A A ND B23 B A A ND C 24 B A A A C 25 ND B A ND C 26 ND C A ND D 27 ND C A ND D28 A A A ND B 29 A A A ND A 30 A A A A A 31 A A A ND A 32 A A A ND A 33ND B A ND C 34 A A A A A 35 A A A A A 36 A A A A A 37 A A A ND B 38 A AA ND A 39 B A D ND D 40 B B C ND D 41 C B D ND D 42 D D D ND D 43 ND A AND B 44 ND B A ND C 45 ND B A ND C 46 ND B A ND C 47 ND B A ND C 48 ND AA ND C 49 ND B A ND C 50 ND D A ND D 51 B A A ND B 52 A A A A B 53 ND BA ND C 54 ND C A ND D 55 D B A ND D 56 A A A A A 57 B A A A B 58 A A A AA 59 A A A ND A 60 A A A ND D 61 A A A ND B 62 A A A ND B 63 A A A ND C64 A A A ND A 65 A A A ND A 66 A A A A A 67 A A A A A 68 B A A ND C 69 BA A ND C 70 A ND A A B 71 A ND A A B 72 A ND A A B 73 A A A A A 74 A A AB B 75 D C B ND D 76 A A A ND A 77 A A A A A 78 A A A ND A 79 A A A ND B80 D D D ND D 81 B A A ND C 82 B A A ND B 83 B ND A A B 84 C ND A A C 85B ND A A B 86 A ND A A C 87 B ND A A C 88 A ND A A B 89 A ND A A B 90 BND A A C 91 B ND A B C 92 A ND A A B 93 C ND B C D 94 A A A ND A 95 A NDA A B 96 D ND B B D 97 B A A ND B 98 A A A ND A 99 C ND D D D 100 ND NDND ND ND

1-254. (canceled)
 255. A method for treating non-small cell lung cancer(NSCLC) with one or more insertion mutations in the exon 20 domain ofthe epidermal growth factor receptor (EGFR) comprising administering toa subject in need thereof, a therapeutically effective amount ofCompound (I) having the following structure:

or a pharmaceutically acceptable salt thereof.
 256. The method of claim255, wherein the subject is an adult human subject.
 257. The method ofclaim 256, wherein the therapeutically effective amount of Compound (I)or a pharmaceutically acceptable salt thereof is about 0.1 mg to about500 mg per day.
 258. The method of claim 257, wherein thetherapeutically effective amount of Compound (I) or a pharmaceuticallyacceptable salt thereof is administered orally.
 259. The method of claim257, wherein the therapeutically effective amount of Compound (I) or apharmaceutically acceptable salt thereof is administered once, twice,three times, four times, five times, or six times per day.
 260. Themethod of claim 259, wherein the therapeutically effective amount ofCompound (I) or a pharmaceutically acceptable salt thereof isadministered once per day.
 261. The method of claim 260, wherein thetherapeutically effective amount of Compound (I) or a pharmaceuticallyacceptable salt thereof is administered orally.
 262. The method of claim261, wherein the therapeutically effective amount of Compound (I) or apharmaceutically acceptable salt thereof is administered in one or morecapsules.
 263. The method of claim 262, wherein each capsule comprisesgreater than about 80% w/w of Compound (1) or a pharmaceuticallyacceptable salt thereof.
 264. The method of claim 263, wherein eachcapsule comprises greater than about 90% w/w of Compound (I) or apharmaceutically acceptable salt thereof.
 265. The method of claim 262,wherein each capsule comprises less than about 0.05 g, and more thanabout 0.04 g of Compound (1) or a pharmaceutically acceptable saltthereof.
 266. A method for inhibiting EGFR with one or more insertionmutations in the exon 20 domain in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount ofCompound (I) having the following structure:

or a pharmaceutically acceptable form thereof.
 267. The method of claim266, wherein the subject is an adult human subject.
 268. The method ofclaim 267, wherein the therapeutically effective amount of Compound (I)or a pharmaceutically acceptable salt thereof is about 0.1 mg to about500 mg per day.
 269. The method of claim 268, wherein thetherapeutically effective amount of Compound (I) or a pharmaceuticallyacceptable salt thereof is administered orally.
 270. The method of claim268, wherein the therapeutically effective amount of Compound (I) or apharmaceutically acceptable salt thereof is administered once, twice,three times, four times, five times, or six times per day.
 271. Themethod of claim 270, wherein the therapeutically effective amount ofCompound (I) or a pharmaceutically acceptable salt thereof isadministered once per day.
 272. The method of claim 271, wherein thetherapeutically effective amount of Compound (I) or a pharmaceuticallyacceptable salt thereof is administered orally.
 273. The method of claim272, wherein the therapeutically effective amount of Compound (I) or apharmaceutically acceptable salt thereof is administered in one or morecapsules.
 274. The method of claim 273, wherein each capsule comprisesgreater than about 80% w/w of Compound (I) or a pharmaceuticallyacceptable salt thereof.
 275. The method of claim 274, wherein eachcapsule comprises greater than about 900% w/w of Compound (I) or apharmaceutically acceptable salt thereof.
 276. The method of claim 275,wherein each capsule comprises less than about 0.05 g, and more thanabout 0.04 g of Compound (I) or a pharmaceutically acceptable saltthereof.